Prof. Reza-ul Jalil
Prof. Reza-ul Jalil, Dept. of Pharma. Tech. DU.
⇒ INTRODUCTION TO PHARMACEUTICAL EXCIPIENTS ⇒ MAJOR GROUPS OF EXCIPIENTS USED IN DOSAGE FORMS ⇒ COLORING AGENTS ⇒ FLAVORING AGENTS ⇒ ANTIOXIDANTS ⇒ ANTIMICROBIAL PRESERVATIVES ⇒ SOLVENT / VEHICLE ⇒ SURFACTANTS ⇒ BUFFERS ⇒ EXCIPIENTS IN TABLETS ⇒ POLYMERS ⇒ FLAVORS AND FLAVOR MODIFIERS
Prof. Reza-ul Jalil, Dept. of Pharma. Tech. DU.
INTRODUCTION TO PHARMACEUTICAL EXCIPIENTS
DEFINITION OF EXCIPIENT The term comes from the Latin word excipients, present participle of the verb excipere which means to receive, to gather, to take out. This refers to one of the properties of an excipient, which is to ensure that a medicinal product has the weight, consistency and volume necessary for the correct administration of the active principle to the patient. In 1957, excipients were defined as ‘the substance used as a medium for giving a medicament’, that is to say with simply the functions of an inert support of the active principle or principles. Again, in 1974 they are described as ‘any more or less inert substance added to a prescription in order to confer a suitable consistency or form to the drug: a vehicle. This historically somewhat limiting definition referred to those substances employed in the preparation of pills, a now obsolete pharmaceutical dosage form later replaced by tablets and capsules. Natural products, such as molasses and honey, were long employed in the preparation of pills up to 1940 and USP 10 also mentioned lactose, glucose, lycopodium, glycerin and gelatin. To the function of simple vehicle, galenic science then added that of adjuvant in the carrying and release of the active principle of the formulation. Looking at the matter from this angle, the United States’ National Formulary of 1994 states that an excipient is any component other than the active principle added intentionally to the medicinal formulation, or ‘everything in the formulation except the active drug’. The following general criteria are essential for excipients:
• physiological inertness; • physical and chemical stablility; • conformance to regulatory agency
• no interference with drug
• absence of pathogenic microbial
• commercially available at low cost.
In reality, no single excipient would satisfy all the criteria; therefore, a compromise of the different requirements has to be made. For example, although widely used in pharmaceutical tablet and capsule formulations as a diluent, lactose may not be suitable for patients who lack the intestinal enzyme lactase to break down the sugar, thus leading to the gastrointestinal tract symptoms such as cramps and diarrhea. The role of excipients varies substantially depending on the individual dosage form.
Prof. Reza-ul Jalil, Dept. of Pharma. Tech. DU.
Provide the drug in a form for absorption or other delivery to the target. regardless of composition or mode of use. Few if any active pharmaceutical ingredients have properties that allow incorporation in units that meet all these criteria. Be convenient to take or administer. Accuracy of dose Where the active ingredient is very potent (i. precision and accuracy of the dose. Medicinal dosage forms. For a diluent to function in this way it must form a homogenous blend with the drug. It is also invariably present in medications for topical or transdermal application. dose is low). with the object of improving the bioavailability and consequently the efficacy and tolerability of the medicinal drug.4
Prof. and behavior of excipients is a prerequisite to the successful design. These are indispensable components of medicinal products and. Therefore. virtually every medicinal product is a combination of the drug substance and excipients. Water may be considered a ‘‘diluent’’ in liquid presentations as it provides the required dose in a volume that can be accurately dispensed or administered. which is so important both in the manufacturing phase and to control the release of the active principle. Dept. Modern pharmaceutical technology also requires verification of the physical state of the excipient. it is necessary to add other materials to make good any shortfalls.
Page. 3. it may be necessary to disperse the drug in a ‘‘diluent’’ or bulking agent. function. DU. Be manufactured by a process that does not compromise performance and that is reproducible and economical.
. Issues such as regulatory acceptability. of Pharma. in most cases comprise the greatest proportion of the dosage unit. The requirements listed above can be
considered the prime reasons for including excipients in dosage forms since they relate directly to product performance. the accuracy of the dose may be compromised. Otherwise accuracy of dose cannot be guaranteed. Liquid or semisolid preparations may require the presence of ancillary excipients to effect solvation or dispersion of the active ingredient. must meet the following requirements that underpin efficacy.e.ROLE OF EXCIPIENTS Among these roles are to be remembered those of guaranteeing the stability. 2. Likewise. It goes without saying that knowledge of the composition. low-dose medications for inhalation as dry powders may have the drug dispersed in or otherwise associated with an inert ‘‘carrier’’ or flow aid. improving the organoleptic characteristics and the patient’s compliance. 4. act as a vehicle for other molecular interactions. Such properties illustrate how a material that resolves one problem may pose others that in turn require the presence of additional excipients. formulations containing drugs in the suspended state may require viscosity-enhancing agents or other additives to ensure that the drug remains homogenously dispersed. and quality: 1. Otherwise. In particular. Water can be one of the most problematic companion materials in a dosage form because of its capability to promote hydrolysis. Retain quality throughout the shelf life and usage period. development and manufacture of pharmaceutical dosage forms.. Otherwise. or simply be a medium for microbial growth. 5. safety. Contain an accurate dose. environmental effects and impact on cost of the product are also important selection criteria. Consequently. Tech. quantities being filled into capsules or dies for tableting may be so low that normal filling and other process variations translate to excessive variation in unit drug content. Reza-ul Jalil.
Tech. Such approaches will be discussed later in this chapter.5
Dissolution in the gastrointestinal (GI) tract following oral dosage. sweeteners. Passage to pulmonary or nasal cavities (inhalation products). the drug must leave the dosage form for absorption or other delivery to the target. and effects of additives on the barrier properties of the skin or mucosal surface. pH. Dissolution or dispersion of drug in such materials provides a substrate for lipolysis. thereby maximizing efficacy or minimizing side effects.
Release of drug from the dosage form Once a medication is ingested. The propensity of the drug to migrate from the formulation to the application surface is affected by factors such as lipophilicity of the vehicle. particularly to younger patients. in chewable dosage forms. resulting in an emulsion of drug and lipid that provides enhanced surface area for dissolution and absorption. Cellulose ethers. or taste-masking agents may be present in liquid oral products. or help dispersion and dissolution prior to passage to the systemic circulation. or even specific cells. More complex release patterns involve using excipients to modify release from the dosage form to delay onset of action or otherwise modify the pharmacokinetics of the drug.
‘‘release’’ into a dosage form involves adding a disintegrant to the tablet or capsule formulation so that on ingestion the compact breaks up and drug is released for dissolution and absorption. Partitioning to the skin in the case of topical or transdermal preparations. organ. Excipients that are bioadhesive or that swell on hydration can promote absorption by increased contact with epithelial surfaces. drug solubility in the formulation. designing
Prof. Benzyl alcohol is employed for this purpose.User or patient convenience Drugs that are bitter or otherwise unpalatable. Reza-ul Jalil. In its simplest form. DU. and synthetic acrylic acid polymers have been evaluated for such purposes. flavors. Some drugs given by injection cause local pain due to high volume. Their presence may be even more crucial with more esoteric forms that must be delivered to a tissue. However.
. Researchers are developing excipients that act as ‘‘homing devices’’ to guide drugs to designated targets. The range of materials
Page. and administered as oral liquids may be unacceptable. and in effervescent or dispersible tablets that are constituted as liquids prior to use. Excipients can influence delivery from topical and transdermal medications. Compliance and therefore efficacy may be compromised unless the product can be made more palatable. of Pharma. Thus. An additive that evinces a local anesthetic effect may relieve such discomfort. This may involve the following: Oral absorption enhancement Oral absorption is indirectly aided by excipients that promote release of drug from the dosage form. Excipients that promote absorption per se are less widely used. Dept. or otherwise administered. In the case of hydrophobic drugs. applied to a target area. gums of natural origin. tonicity. by prolonging residence time in the stomach. dissolution may be aided by wetting agents. lipids have been used to enhance absorption of hydrophobic active ingredients.
Excipients can ensure that such delivery is expeditious and consistent. etc. or by delaying intestinal transit.
EXCIPIENTS AS STABILIZERS Product quality can be compromised during manufacture.available and their differing viscoelastic and rheological behaviors mean that it is possible. Stablization strategies include the following:
• Formulation with an excipient whose
Enhancers for Other Modes of Absorption Many physical and enzymatic barriers can prevent successful delivery of active pharmaceutical ingredients by noninvasive. thereby optimizing conditions for mucosal diffusion. Equally important stabilizers include preservatives in liquid products to prevent microbial growth and buffers to provide an environment conducive to good stability where degradation is pHrelated. density.’’ Polyethylene glycol also has been shown to stabilize an ointment formulation by preventing formation of inactive rearrangement products. Transdermal delivery is a case in point. The causes of deterioration can be manifold and product-specific.
Page. Entry via nasal or buccal mucosa allows the delivery of peptides or other labile drugs that are highly potent (low-dose drugs) and that do not have steep doseresponse relationships.
light absorption spectrum overlaps that of the photolabile drug. Tech. It is not surprising. The skin. to develop delivery units with balanced properties so that adhesion. Excipients can contribute to or cause such changes unless carefully screened for possible interactions in preformulation studies. transport. by judicious admixture. Reza-ul Jalil. hydration. particularly the stratum corneum presents a formidable barrier to diffusion. Chelating agents also are used as stabilizers to prevent heavy metals from catalyzing degradation. DU. therefore. This is the socalled spectral overlay approach. Excipients that enhance nasal absorption include phospholipids to enhance mucosal permeability and agents that imbibe water and become mucoadhesive (e. Dept. in adjacent molecules.
• Using an excipient that ‘‘hinders’’
association of groups in the same molecule. There are several reports of cyclodextrins effecting such ‘‘steric stabilizations. glyceryl mono oleate). In addition.
• Using an antioxidant in formulations that
are susceptible to degradation by oxidation. can be tailored to the drug in question and the physiological characteristics of the target delivery site. non-oral routes.g. largely
. EXCIPIENTS AS PROCESS AIDS The vast majority of medicinal products are manufactured by high-speed. that there is great interest in excipients that can overcome such obstacles. Materials used to enhance its permeability have ranged from simple solvents such as ethanol or propylene glycol to aromatic chemicals such as terpenoids. drug release rate. etc. the gelling agents hydroxypropyl cellulose and polyacrylic acid promote absorption of insulin in dogs. They include microbial spoilage or chemical transformation of the active or physical changes that alter performance in vivo. or in the vehicle that can interact and cause degradation. Such penetration enhancers appear to work by disrupting the lipid domains in the stratum corneum that reduce permeability. This approach has been particularly successful in vitamincontaining products. Deterioration can compromise safety or make the medication less attractive. which means it may not be used.. of Pharma. Absorption enhancement requires increased contact time and reduced clearance rate (in the case of nasal delivery). storage or use.
of Pharma. plant (e. silica) and 4. Most are derived from plant. they too have their own thermo-dynamic activity
Page. gelatin. stearic acid). new classes of excipients have now become available. They are widely used for these purposes in inhalation formulations of antiasthmatic agents such as salbutamol and budesonide. Materials such as colloidal silica improve flow from hopper to die and aid packdown in the die or capsule shell. lactose. povidone. alone or in combination. Like pharmaceutical drugs. animal.g. Dept. Looking at the matter from this angle. and other process equipment. Tech.
• Excipients that aid powder flow in tablet
particle size) can enhance flow or act as a ‘‘carrier’’ from the dose unit (usually a capsule) through the inhalation delivery device to the oral cavity on inspiration. calcium phosphate. It is common to use ‘‘cryoprotectants’’ such as sugars.
• ‘‘Flow aids’’ also can help performance
in cases where the delivery device is an integral part of the medication. sugars. In order to carry out the numerous functions required. militates against good flow.7
compact. adapted to the manufacture of highperformance pharmaceutical dosage forms. or mineral origin (microcrystalline cellulose.) Their origin and use do not often guarantee the quality required by the pharmaceutical industry. whether on dry granulation (slugging) prior to tableting or on tablet compression. Products for pulmonary delivery are often formulated as dry powders that are inhaled via the oral cavity.automated processes for reasons that are related as much to safety and quality as to cost of goods. 3. arginates). synthesis (e. lactose. excipients can no longer be considered mere inert supports for the active principles. and such as to cause possible action due to their mass.
• Agents such as human or bovine serum
albumin that are used in the manufacture of biotechnology.g.
• Stabilizers to protect the drug from
processing conditions that might otherwise be deleterious.
• Compression aids to help form a good
ORIGINS AND SOURCES OF EXCIPIENTS Excipients are of various origin: 1. but essential functional components of a modern pharmaceutical formulation.g. which must therefore submit them to more thorough -going analytical controls. derived from old and new materials.
. filters. which may be vital for efficient delivery to the bronchial target area. or magnesium carbonate).g. PEGs. Materials such as lactose or mannitol (of appropriate
Prof. polyhydric alcohols or dextrans in lyophilized parenteral biotechnology products to prevent inactivation during freezing. polysorbates. Excipients that aid in processing include the following:
• The almost universal use of lubricants
such as stearates in tablets and capsules to reduce friction between moving parts during compression or compaction. It is also to be borne in mind that the ratio of their weight to that of the active principles is usually very high in a formulation. DU. The fineparticle nature of the medicinal agent. These avoid adsorption of the protein to flexible tubing. starches.based products. animal (e. Accuracy and consistency of fill and associated dose is thereby improved. 2. etc. cellulose. mineral (e. Reza-ul Jalil.
or capsule manufacture.
disintegrants. In Fig. this view is out-dated and. can contribute to reactions leading to degradation or to interactions between the drug and the excipient. we shall examine three issues that may compromise the safety of pharmaceuticals: (a) production. The physical type of interaction can modify. Today it is reckoned that over one thousand different materials are used in the pharmaceutical industry to fulfil its various requirements such as diluents. The third category covers new compounds. Indeed. which may be the cause of frequent and sometimes notable ‘adverse effects’. (b) pharmaceutical-excipient interactions. DU. the speed of dissolution or the uniformity of the dosage of a solid formulation. as they were cheap ingredients viewed solely as inert supports for medicaments. 1. They are chemically heterogeneous compounds that go from simple molecules (water) to complex mixtures of natural. defined as ‘the physical. Tech. Interactions occur more frequently between excipient and active principle than between excipient and excipient and these interactions can be of two types. Dept. Reza-ul Jalil.which. physicochemical and biopharmaceutical properties’ of the same. The intermediate category (essentially new excipients) covers compounds obtained by means of the structural modification of the excipients already approved or those already used in the food or cosmetic industries. Today. 2. we may say that excipients are rather more than the sugar in the pill. From the regulatory point of view. distribution and use. some materials can adsorb drugs to their
Page. the importance of excipients in pharmaceutical formulations has generally been underestimated. never previously used in the pharmaceutical field and it is growing rapidly due to the present interest in modified-release formulations and the requirements of the modern high productivity compressing/tabletting machines. for example. Safety has always been the most important requirement and the most studied when dealing with pharmaceutical drugs.8
PRINCIPAL REQUIREMENTS OF EXCIPIENTS Historically.
DRUG–EXCIPIENT INTERACTIONS Excipients constitute the mass or greater volume in the usual enteral or parenteral formulations and. colouring agents. In the first category (approved excipients) we find the compounds originating from the food industry (generally recognised as safe: GRAS) or that have been present in pharmaceutical products for a very long time. though generally low. on the basis of
Prof. because their inertia and innocuity were taken for granted. of Pharma. etc. At this point we may well ask ourselves what the basic requirements of a modern pharmaceutical excipient are. lubricants.
what we have said above. 1 the three essential requirements of active principles are compared with those of excipients. may be subdivided into three categories. they often contain reactive functional groups that may give rise to chemical and physical transformations. To this end. The requirement of therapeutic efficacy for drugs is replaced by that of functionality for excipients. sweeteners.
. semisynthetic or synthetic substances. 3. bulking agents. and (c) toxicity. Fundamental for both are quality and safety. Less attention has been devoted to the safety of excipients.
can slow down dissolution and therefore bioavailability.g. Despite the earlier account of excipients acting as stabilizers. such as ampicillin. Degradation may be caused by interaction between functional groups in the excipient and those associated with the drug. Many small-molecule drugs contain primary. Other.g. However. may give rise to oxide-reduction and the formation of free radicals (e. sodium alginate and neomycin cation precipitate in an acqueous solution. One example is the hydrolisis of the imino nitrogen link of nitrazepam with consequent disactivation of the drug.). Such effects may be accentuated during processing.
Page. giving rise to reactions such as hydrolisis. Excipients may contribute to degradation even when not directly interacting with active moieties. can lead to the degradation of the drug and/or the formation of the so-called degradation impurities. magnesium stearate) which. Soluble materials may alter pH or ionic strength. Tech. Another type of interaction may occur between the carbonilic groups of a widelyused excipient like poly-vinylpyrrolidone. Physical interactions between drug and excipient also can compromise quality. or tertiary amino groups and these have the propensity to interact with aldehydic groups in sugars or volatile aldehydes present as residues. Even when degradation is modest. trans esterification. One example is the presence of polymeric forms in beta-lactam drugs. In solid forms which contain hygroscopic components. thereby accelerating hydrolytic reactions in liquid presentations. and pharmaceuticals containing donor groups of hydrogen. light. in anhydrous conditions. thus causing problems of incompatibility. the presence of humidity must be controlled and reduced. Reza-ul Jalil. In this way. thus increasing the active surface and consequently the wettability and speed of dissolution. . heat. like famotidine and atenolol. when evaluating potential pharmaceutical-excipient interactions. behaves
like a Lewis acid. when finely dispersed on the particles of the active principle. DU. lowering the title of the active principle and generating dangerous impurities. isomerisation and polymerisation. of Pharma. it is possible that the formed degradation products may compromise safety. which are more likely to occur with certain types of excipients. secondary. whereas in the case of solid formulations they are low. which are thought to be responsible for dangerous allergic reactions. Chemical interaction can result in degradation of the drug substance to inactive moieties with loss of efficacy where degradation is excessive. One example is that of lipophilic lubricants (e. Dept. if not negligible. on the other hand. epimerisation. it must however be considered that the kinetics of chemical reactions involving solutions are very high. Interaction between chloramphenicol stearate and colloidal silica during grinding led to polymorphic transformation. because water is the preferred and prevalent solvent in liquid formulations. lipidic peroxidation). The chemical type of interaction. less frequent. when activated by traces of catalysts (heavy metal ions. .
Prof. in which case the drug is released with difficulty and assimilation is compromised. Even silicon dioxide (SiO2). it is fair to state that there are far more cases on record of excipients adversely affecting quality.surfaces. The contrary effect may be encountered when the forces of attraction are strong. etc. Adsorption of drug by microcrystalline cellulose resulted in drug dissolution being less than complete. The most frequently encountered reaction is hydrolisis. Even the presence of oxygen. Ionisable pharmaceuticals may react with ionised soluble excipients giving rise to the formation of insoluble products due to charge interactions.9
. reactions are photolysis.
which represents the dose that does not carry risks to the population if taken every day for a life-time. the subject may be organised as follows:
toxic effects encountered in the whole population.
. The JECFA usually terminates its toxicological evaluations with the publication of an admissible daily intake (ADI). natural or synthetic substances when a certain dose is exceeded. To simplify matters.10
TOXICITY OF EXCIPIENTS A discussion of the toxicity of the excipients employed in pharmaceutical formulations is certainly a difficult and extremely diversified task. especially those that are used as food additives. It is important to identify and characterize such ‘‘process stresses’’ during dosageform development and tailor processing conditions accordingly. among which phenylketonuria and lactose intolerance) or genetic predisposition (among which diabetes and allergic pathologies). Stabilization may be possible by drying prior to use. has to do with phenomena that are often independent of. Dextrose is widely used in parenteral nutrition solutions or as a tonicity modifier in other parenterals. sterilization by autoclaving. That is to say. or only marginally dependent on. but loss of water may make it a less effective compression aid. other substances. given that no adverse effects have been encountered in man. Microcrystalline cellulose is a partially depolymerized cellulose that is partcrystalline/part non-crystalline and hygroscopic. The excipients that have been authorised to be used as food additives have been evaluated as regards toxicology by the JECFA (Joint Expert Committee on Food Additives). Dept. In principle. This is assuredly applicable to many compounds. which handles the evaluation of the risk from consuming additives or contaminants with food. This dose is expressed in mg (or microg) per kg of daily
Page. DU. that have been used for decades now. may cause significant degradation product formation because of the high temperature involved. If the drug is moisture sensitive. such as genetically-transmitted pathologies (metabolic illnesses. At the other extremes of processing. The second category. exactly as in the case of pharmaceutical excipients. In the case of additives. degradation may follow. Thus. toxic effects encountered only in specific populations. Sterilization by autoclaving can cause isomerization to fructose and formation of 5-hydroxymethyl furfulaldehyde in electrolyte-containing solutions. can be considered ‘safe’. while of short duration. Reza-ul Jalil.
Prof. with associated reduction of pH and unfolding of gamma interferon. which take into particular consideration the results of long-term toxicological studies. Adsorbed water is not held in any ‘‘bound’’ state but will rapidly equilibrate with the environment during processing or storage. excipients ought to be subjected to the same toxicity studies as those requested for active principles. water can be sequestrated by a more hygroscopic active ingredient. whereas contaminants are substances that can be vehicled by the food chain. our preferred source of toxicological data has been the JECFA’s conclusions. of Pharma. Tech. succinate buffer was shown to crystallize during the freezing stage of lyophilization. it is possible that in a dosage form. given the ubiquitousness of the distribution of pollutants in the environment. so as to protect the population from undesirable effects. however. they are events linked to specific characteristics of the subjects. the dose.For instance.
Into the first category fall all the adverse effects proper to chemical. their use is voluntary and has a technological reason. However. In this article.
constant vigilance is
Prof. As recently as 1996. storage conditions. and quality audit systems should mean that adulteration is largely a thing of the past. Reza-ul Jalil. The value of the ADI is extrapolated from studies conducted in laboratory animals. Thankfully. paraffins. efficacy and safety of active principles but only recently has the necessity emerged of examining not only the quality and performance but also the safety of the excipients.11
IMPURITIES IN EXCIPIENTS Excipients. and flavors oxidize. For a long time now. Residues in excipients can affect quality and performance by interacting with the drug or other key components. whether in solid forms. suspensions or solutions. To establish the total daily dose. of Pharma. Acetate buffer is volatile at low pH and can be lost during the drying stages of lyophilization. Dept. degradation products or other structural deviants formed during manufacture. a combination of better analytical techniques. The ideal excipient should be able to fill numerous and important functions. Oils. Preservatives such as benzoic acid or the para hydroxybenzoates are volatile and can be lost during product manufacture if the process involves heating. The problem is not simple if one considers that in countries like the United States. permeability. Tech.
STABILITY OF EXCIPIENTS Excipients can lose quality over time. renal failure in children in Haiti was ascribed to use of glycerol contaminated with diethylene glycol in a liquid paracetamol product. DU. much attention has been paid to the required quality. Such behaviors reinforce the need to know the behaviors of excipients as well as of the active ingredient so that appropriate processing. This can lead to changes in elasticity. Polymeric materials used in film coating or to modify release from the dosage form can age due to changes in glass transition temperature. and the patient’s ‘compliance’.
. Furthermore. cellulose gums may lose viscosity. it should possess particular chemical. Reducing sugar impurities in mannitol were responsible for the oxidative degradation of a cyclic heptapeptide. and hydration rate and associated changes in release properties or appearance.
necessary. CONCLUSIONS Medicinal products can be considered a dosed combination of two types of constituents: the active principles and the excipients. like drug substances contain process residues. The latter are the more important as far as weight is concerned. About one fifth of them are present in the respective Pharmacopoeiae. it was not unusual for adulterants to be added to ‘‘bulk up’’ the commodity. However. vendor certification programs. dividing the highest dose without toxic effects in the animal by a safety factor (generally 100). physical and mechanical characteristics.weight per day. we should multiply this number by the bodily weight (usually reckoned as 60 kg). so as to optimise the formulation’s ‘performance’ both during the manufacturing phase (manufacturability) and when used by the patient. This multiplicity of roles fits very ill with the traditional galenic view. of more or less complex structure and belonging to different chemical classes. Historically. which list the pharmaceutical quality requirements but
Page. Japan and Europe there are now in use over a thousand excipients of varying origin. first among which that of guaranteeing the dose. stability and release of the active principle. that saw these ‘non-medicinal ingredients’ as chemically and pharmaco-toxicologically inert. and ‘‘use by’’ periods are stipulated where necessary. Loss during product storage is also feasible if containers are permeable to passage of organic vapors.
Prof. polishing agents Tonicity agents Vehicles Viscosity imparting agent Wetting agent. much less do they embark on questions of safety. or else they were already used in pharmaceutical products that had been in therapeutic use for a very long time. Some information on this aspect may be gleaned from some texts. DU. Reza-ul Jalil. Tech.not physical chemistry requirements.
MAJOR GROUPS OF EXCIPIENTS USED IN DOSAGE FORMS
Acidifying agent Adhesive agent Alkalizing agent Adsorbent Aerosol propellants Air displacement Anti foaming agents Antifungal preservatives Antimicrobial preservatives Anti oxidants Buffering agents Chelating agents Coating polymers Coloring agents Emulsifying agents Flavoring agents Humectants Ointment bases Carriers for dry powder inhalers Solvents Suppository bases Surfactants Suspending agents Sweetening agents Tablet anti adherents Tablet binders Tablet/capsule diluents Tablet coating agents Tablet disintegrants Tablet glidants Tablet lubricants Tablet-coated.
Page. of Pharma. This under-estimation of the safety aspect is also a consequence of the fact that the first excipients were taken from the food industry and therefore considered ‘as safe’. Today it is required that any chemically new product whose effects on man are not known must pass all the toxicological tests envisaged for an
active principle before it can be accepted as an excipient.12
or extracted. All lakes contain approximately 1523% by weight residual moisture. since they do not have a direct influence on the therapeutic effect of a dosage form.
Definition of Terms
Dyes are substances which impart color to an object. food and cosmetic colorants were obtained form mineral. Synthetic coloring agents. date back to the mid-19th century. animal and vegetable sources. According to the Code of Federal Regulation of USA. or cosmetic. There are colored and white pigments. from a vegetable.
In this context the use of the world dye implies a pigment implies a material that is insoluble but disperses in the film-coating solution. The need to identify tablets in order to minimize the risk of confusion to the patient is an important factor to be considered in formulation. of Pharma. The cause of color is attributed to the presence of certain chromophore groups within the color producing molecule. is capable (alone or through reaction with other substances) of imparting color. Colorants are preparations of dyestuffs meant for coloring. As soon as all the dye has been absorbed the precipitate is washed and filtered before being dry ground to the desired particle size. soluble dyes dissolve in specified liquids.
Page. drug. Pigments are solid dyestuffs or mineral colors which unfold their color effect when finely dispersed. The importance of colorants and flavoring substances is frequently undervalued.O. and for purposes of product distinctiveness is important. and a major industry developed in the field of coal-tar dyes.COLORING AGENTS
DEFINITION A material that is a dye.N = N+ . synthetic or otherwise. Moreover. they are helpful in identifying unpacked dosage forms. particularly those taking multiple medication. Approximately 90% of color additives in prescription and OTC drugs are synthesized from aniline that is currently obtained from petroleum or petroleum products. or otherwise derived with or without intermediate or final change of identity. The pigmentary properties and the shade of the aluminum lakes depends a great deal on the preparation of the alumina. DU. Reza-ul Jalil. Identification of the product by the manufacturer and therefore act as an aid (not a replacement) for existing GMP procedures. Colourants for film-coated tablets have to a greater or lesser extent opacifying properties which are useful when it is desired to optimize the ability of the coating to protect the active ingredient against the action of light. These chromophores include the -N = N=C=S -N=O . inorganic pigments and miscellaneous natural colorants. bicarbonate or carbonate.g. Chemistry of color:
• • •
the synthetic organic dyes and their respective lakes. that when added or applied to food. some of which is bound as water of hydration and all are insoluble in most solvents. a by-product of coal distillation. color additives are: "Any substance. enhance the acceptance of the product and therefore contribute substantially to a reliable therapy. Tech. with aluminum or calcium) or surface fixation. is capable of imparting a color thereto". the processing conditions during the deposition of the dye and the extent of grinding. The calculated quantity of dye necessary to achieve the required dye content is added to the alumina slurry and aluminum chloride solution added to effect lakeing. The use of coloring agents in pharmaceutical preparations for purpose of esthetics.13
. Color provides a relatively simple and convenient solution to this problem.
Synthetic organic dyes and lakes If the water-soluble organic dye is precipitated as its aluminum salt on to alumina by the addition of aluminum chloride then the pigment so formed is known as an aluminum salt by the addition of sodium hydroxide. Color lakes are water-insoluble colorants obtained from soluble. or other substance made by a process or similar artifice. isolated. They do. so is widely used in tablet film coating. or to the human body or any part thereof. pigment. as sensory adjunct to the flavors employed.
coated products and film-coated tablets is essentially the same. Colorants commonly used can be divided into three groups. mineral or other source and when added or applied to a food. The coloring process for sugarPHARMACEUTICAL EXCIPIENTS Before the development of synthetic color additives. drug. Dept. a derivative of benzene produced from coal tar. They reinforce brand imaging by a manufacturer and thereby decrease the risk of counterfeiting. however.N+<OO (AZO) (THIO) (NITROSO) (AZOXY) (NITRIO)
Aesthetic issues in dosage form design. Colourants also aid in the identification of individual products by patients. By 1900. or cosmetic or to the human body or any part thereof. animal. The amount of dye precipitated on the alumina is generally in the region of 10-40% by weight. organic dyes by salt formation (e. nearly 700 colors had been synthesized from aniline. which were extracted from coal tar.
Lakes -. -OH The light of the visual spectrum which is not absorbed by the compound is transmitted or reflected and the compound assumes the color of the unabsorbed light.CH =N =C=O =C=C
(AZO METHINE) (CARBONYL) (ETHENYL)
a) certified colors . green 2 FD&C yellow 1. -. However. Dept. The auxochromes are capable of forming ionizable salts. FD&C red 3 Methylene blue
3. Thus if a compound absorbs all light of the visible spectrum except that viewed by the eye as red it will appear to be that color. of Pharma. -. Phthalein Dyes 4.Only few dyes are soluble in alcohol. Thiazine dyes 5. The auxochromes include the basic . D & C and D & C for external use.FD&C dyes are water soluble ( and insoluble in most organic solvents). Drug and Cosmetic act of 1938 (US) broadened the scope of certified colors.. It is again two types: -.most natural colors.FD&C green 1. sulfur.dyes are made soluble in glycerin and then propylene glycol. it is often possible when water is added in the process. Indigo dyes Stability of dyes:
Prof. to add the dry color to the batch and depends upon the added moisture and heat to dissolve the color in processing. or a salt prepared from one of the water soluble straight colors by combining such color with the basic radical aluminum or calcium". Reza-ul Jalil.When anhydrous conditions are of important considerations. Any substance causing a decrease in the ionization will reduce the intensity of the color.
-Scarlet red. b) uncertified colors .Dyes are available in different form: Powder/ Granular/ Plating color/ Wet dry (blends)/ Diluted (cut blends)/ Liquid (aqueous)/ Liquid (non aqueous)/ Pests. Tech. containing three categories: F D & C. They may be present in the molecule. glycerin and propylene glycol are used as solvent. -. Dye color by being dissolved in the solvent and the pigment (lake) by dispersion. The dyes manifested their coloring power by being dissolved in the water medium. Azo dyes Orange 2. Chemical classification of dyes: 1.
Page. The Food. Triphenylmethane 6.Good coloring technology recommends that the dyes solubilized before addition of colored product. The alumina hydrate or aluminum hydroxide substratum is insoluble so what is produced is an insoluble form of the dye . FD&C lakes: The color regulations defined FD&C lake as "Extension on a substratum of alumina. The dye ion exhibits greater resonance than the parent molecule. carbon) Mica Pyrophylite Chromium oxide greens (chromic sesquioxide) Vegetable Canthaxanthin (natural beta carotene) Saffron (Crocus sativis) Indigo (Indigo plant) Chlorophyll (Green plant) Beet juice (beets) Xanthantine (microalgae) Tagetes (Aztec marigold petals) Caramel (burnt sugar) Grape color extract (Concord grapes) Alizarin (Madder plant) Annatto extract (annatto seed) Turmeric (Curcuma longat) Logwood extract (leguminous trees) Animal Guanine (from fish scales) Tyrian purple (snails) Cochineal (insect) Carmine (lake of cochineal) CLASSIFICATION PHARMACEUTICAL EXCIPIENTS
2. -. yellow 2 FD&C blue 2
7.synthetic and mineral colors approved by FDA. This cause deepening of the color. whether for their therapeutic or coloring properties. Na-carbonate. Nitro dyes -
. DIFFERENT SOURCES OF COLORS: Synthetic There are many synthetic dyes currently used (see below) Mineral Alumina (aluminum hydroxide) Red ferric oxide Yellow ferric oxide Titanium dioxide Azurite Carbon black Ultramarine blue (kaolin.Dyes -.N<RR . Acridine Dyes Acriflavine
Other substituent groups called AUXOCHROMES.NH-R -NH2 acidic -SO3H -COOH. DU. Most of the dyes used in pharmacy. are salts of acid or basic dyes.14
. This is the basis of many incompatibilities. -. FD&C Red 1.a pigment. Red 2.
Prof. The use of EDTA serves as a protection of color fading. a coal-tar dye that was popular in 1930's for
eyebrows and eyelashes. This permits greater accuracy in measurement and more consistent color production. are the factors of color fading. The ascorbic acid is a such reducing agent. In the dye stage no degradation has been noticed (other than loss in dye strength by absorbing moisture) in storage for 15 years. Coloring technology for pharmaceuticals: -. compatible with the drug and other formulation ingredients. capsules.In general the certified colors can be said to be stable for most uses. -. 4.A colorant becomes an integral part of a pharmaceutical formulation. urticaria. amaranth as well as FD&C Red no 4 and Carbon black were delisted. 3. -. this color additive must be listed on the labels of food and OTC drugs to alert consumers who may be sensitive to it. Classification of Antioxidants: A: Primary antioxidants: oxidation of
• Lash Lure. Dept. 2.or the colorant may be admixed as part of the dry powder mixture for uncoated tablets. then the anitoxidant will be destroyed rapidly by reaction with atmospheric oxigen.
reported by Russians in 1970's. a formulator must select the dyes to be used in a particular formula on the basis of the physical and chemical properties of the dyes available. the A-H chemical bond should be weaker than the R-H bond of the oxidiziable substnce. thermal stability. of Pharma. etc. and its exact quantitative amount must be reproducible each time the formulation is prepared. blindness and death. odorless.
. tasteless and colorless.in addition to esthetics and certification status of a dye.1% dye. decomposition products should be non-toxic and non irritant. -. stable and effective over a wide range of pH. Page. copper. the light stability of the dye in the finished product is good. A* + A* ------> AA A* + R* ------> AR It follwos that for effective stabilization against autoxidation. film coated tablets and chewable tablets contain approximately 0. Since 1980. 5.
act by interfering with the propagationstep of the autoxidtion process. non volatile. zinc. such as. AH + O2 ----------> A* + HO2* It is evident that a primary antioxidant is used up by taking part in the chain process instead of the drug. -.Two areas. such as. DU.
• FD&C Red no 2 (amaranth) caused cancer in rats. -.in contrast. non-toxic and non-irritant at the effective concentration. including asthmatic symptoms. Reza-ul Jalil. adequately soluble in the product. angioedema. especially in persons allergic to aspirin. These include: solubility. in which the majority of the certified FD&C colors show instability are i) in combination with reducing agent and ii) retorted protein materials. -. Tech. pH & pKa values. 7. tin.colorant generally added to liquid preparations ranges between 0.
ANTIOXIDANTS Substances that reduces or inhibits chemicals and drugs in a formulation. -.-.in case of tablets. 8. sugar coated tablets. pH stability. However.With the exception of FD&C Blue no-2 and FD&C red no-3. solid dosage forms such as tablets. if the bond is too weak.the dye must be chemically stable in the environment of the other formulation ingredients and must not interfere with the solubility -.The azo triphenyl methane dyes are easily reduced to colorless compounds.Contact with metals.or else the preparation would have a different appearance from batch to batch. or nasal symptoms. 6.001% depending upon the colorant and the depth of color desired. -. aluminum. light stability (photostable).
• FD&C yellow no 5 (Tartrazine) was suspected of
producing allergic-type reactions. PROPERTIES: 1. Safety of dyes: Some examples:
-. In 1976.0005 to 0. AH + R* -----> RH + A* AH + ROO* --------> ROOH + A* Subsequently the antioxidant radical is annihilated by combination with other antioxidant radical or some other free radical.whenever possible dyes are added to pharmaceutical preparations in the form of dilute solutions rather than as concentrated dry powders. Effective in low concentration. in a few cases caused devastating effects. the color may be sprayed on the formed tablet during the coating process.
Potasium and sodium metabilsulphiets-. Dept. DU. Tech.16
Water soluble Citric acid Tartaric acid Phosphoric acid Ascorbic acid Water insoluble Ascorbyl palmitate Mono-isopropyl citrate palmityl phosphate Mono stearyl citrate PHARMACEUTICAL EXCIPIENTS Prof. Primary antioxidants:
Quinol group Hydroquinon Tocopheorls Hydroxychromans Butylated hydroxy anisol Butylated hydroxy toluene Catechol group Catechol Pyrogallol Nordihydroguaiaretic acid (NDGA) Gallic acid Ethyl gallate Propyl gallate Octyl gallate Dodecyl gallate Nitrogen containing substance Diphenyl amines Casein Alkanolamine esters Amino and hydroxy derivatives of p-phenyl amine diamine Sulphur containing substances Cysteine hydrochloride
B.for acidic solution Bisulphites -. of Pharma.for solution of intermediate pH Sulphites -.for unbuffered and alkaline pH Other examples are: Sulphurous acid Hypophosphorous acid Dextrose
C.Classification of Antioxidants
A. Page. Reza-ul Jalil.
_ Antiseptics: Chemical agents or formulations that can be used as an antimicrobial agents on body surfaces. _ Preservatives: Chemical agents or formulations that are capable of reducing the number of viable microorganisms within an object or field to a level that is safe for its designated use and will maintain the numbers of viable microorganisms at or below a level for the use/ shelf-life of the product. the pH of a formulation determines the types of preservative suitable for inclusion. 4. but are used to reduce the level of microorganisms from the surface of inanimate objects to one that is safe for a defined purpose. Agents such as quaternary ammonium compounds. even if they conform to a pharmacopoeial specification. and are used for this purpose.stable in sterilizing temperature .17
.compatible with other ingredients
ANTIMICROBIAL PRESERVATIVES DEFINITION OF TERMS Disinfectants. antiseptics. the performance of the agents will be variable. antifungal activity is difficult to obtain.. _ Bactericide: A chemical antimicrobial agent that reduces the viability of a population of microorganisms exposed to it.non-volatile Important points: * inactivation of antimicribial agens can be accmplished using polysorbate 80 (tween 80) or lecithin. Certain gram-negative organisms such a Pseudomonas aeruginosa are virtually resistant to these agents. _ Bacteriostasis: A state in which the growth of microorganisms is halted or inhibited. Generally combinations of two gives better results than using single preservative.non-allergenic and non-sensitizing . used at low concentrations in some shampoos. This term is meaningless without specifying the concentration at which this effect is achieved. This term is meaningless without specifying the concentration range over which this effect is obtained.stable against chemical degradation . Broad spectrum of activity: The compounds must possess a broad spectrum of antimicrobial activity against all species of microorganisms and also toward bacterial endospores. yeasts. The following are the properties of an ideal preservative compound and need to be considered when choosing a preservative. It should be noted that terms such as bactericide and bacteriostat should be discouraged.non irritant PHARMACEUTICAL EXCIPIENTS
. Definable in chemical terms: Many of the existing preservatives. the term ‘‘antimicrobial agent’’ has replaced these terms. compounds are generally more active at either acid or alkaline pH. In practice. 2. In practice.broad spectrum and non specific . Combinations of preservatives are sometimes employed to widen the spectrum of activity to include molds.continuing activity .rapid action . bacteria. however. in the USP and EP. Thus. Generally.
Page. Unless it is possible to define and control mixture composition. All these compounds are highly irritant at sterilizing concentrations to be used in pharmaceutical products.capable of incativation or nutrilization for sterility testing . of Pharma. and preservatives are chemicals that have the ability to destroy or inhibit the growth of microorganisms. DU. in these cases contact with the skin is short-lived and irritancy minimal. Often the activity obtained is a function of the mixture composition. Tech.solubel in common pharmaceutical vehicles . phenolics. Formaldehyde is.
PRESERVATIVE IDEALS At present there is no perfect preservative. 1.non toxic . Reza-ul Jalil. Effectiveness: The compounds must be effective over a wide range of pH in order to be effective in all formulations. hypochlorite. These and other terms commonly employed are defined as follows: _ Disinfectants: Chemical agents or formulations that are too irritant or toxic on body surfaces. Attributes desired for antimicrobial preservatives: . _ Bacteriostat: A chemical antimicrobial agent that can prevent the growth of microorganisms within an otherwise nutritious environment. Stablility: The compounds must be stable to light and elevated temperatures for the expected shelf life of the
Prof. 3. and the parabens group possess good activity against grampositive bacteria but little or no activity toward spores. gluteraldehyde. such concentration ranges will vary between different species of microorganisms. and all materials are a compromise of a number of often contrary properties. and ethylene oxide. such as the quaternary ammonium compounds. are mixtures of various homologues. Dept. and endospores. the only compounds that meet this requirement are formaldehyde. Bacteriostatic concentrations do vary between different species of microorganisms.
Reza-ul Jalil.01 1000 USP unit
Prof. In practice this is very difficult to achieve.18
. of Pharma. Dept. DU.5 0.1 0.002 0.5 0. Relatively few compounds are approved for use in opthalmic products due to their high sensitivity towards xenobiotics.0. Solubility: Preservatives should ideally be used at concentrations much lower than that of the main constituents of the formulation. compounds safe for use on intact skin might be hazardous for inclusion in parenteral products.2 0. The effects of pH upon stability should be minimal.
Page. the site of application is critical.
PRESERVATIVES FOR PHARMACEUTICAL DOSAGEFORMS
0. Tech. In this respect. not cause hypersensitivity reactions. In this respect it is worth noting that the preservative Bronopol is stable only in the dark and at an acid pH. 6.02 0. Solubility in oil: Preservatives must not be too oil soluble as this can produce problems in two and threephase systems where the preservative accumulates in the oil and micellar phases and is unavailable for antimicrobial action in the biological (aqueous) phase.product. 8. This can be of crucial importance for a cosmetic product but is less important for medical ones. color.1 .1 0.(%)
For oral use: Benzoic acid Sodium benzoate Methyl Paraben and salts Propyl Paraben and salts Butyl Paraben and salts Alcohol Glycerin Sorbic acid and salts Propionic acid and salts Dehydroacetic acid For parenteral and opthalmic products: Benzalkonium chloride Benzothonium chloride Benzyl alcohol Chlorobutanol Phenyl ethyl alcohol Cresol Chlorocresol Methyl paraben Propyl paraben Phenol Phenyl mercuric nitrate Phenyl mercuric acetate Thiomerosal Polymyxin-B-Sulfate For topical applications: Benzoic acid Phenol Sorbic acid Alcohols (ethyl and propyl) Quarternary ammonium salts Mercurals
0.02 15 -20 45 0. and be non-toxic.5 0. 7. 5. Under alkaline conditions or in the light it rapidly decomposes to give formaldehyde at concentrations that would be ineffective as a preservative. Product incompatibility: Preservatives should not be incompatible with any of the likely excipients within the product formulation. This would include incompatibilities with the container material and also the active ingredients. Also.2 0.5 0. Toxicity: At the concentrations employed. Aesthetics: Preservatives should have no perceptible odor. 10. Volatility: Preservatives should be non-volatile. Their solubility ought to be such that it is possible to add them as a concentrated solution and where there is no danger of creating a saturated solution.1 . 9.0. which might affect the aesthetic qualities of the final product.01 0. or taste. the preservative should be non-irritant.01 2 0.1 0. chloroform is not an ideal preservative as it is lost from the formulation each time it is exposed to air.002 0. Thus.05 0.0. It is worth noting that the oil : water partition coefficient can alter as a function of pH and also as a function of the nature of the oil.3 .
and 4. ketones. provided the transition state is more polar than the reactants themselves. Dimethylacetamide. or tonicity with respect to biologic membranes. and amines. 3. DU. federal regulations require that the specific oil be listed on the label of a product. For example. The use of cosolvents to prepare solution formulations of non-polar drugs is a simple and potentially effective way to achieve high concentrations of drug. The need to employ cosolvents in the formulation of new drugs as solutions for oral. tissue irritation. Ethyl alcohol. 7. aldehydes. Ethyl oleate. refers to the technique of using cosolvents for the stated purposes. Water Miscible Vehicles: (Non-aqueous Solvents) Cosolvents are defined as water-miscible organic solvents that are used in liquid drug formulations to
upon dilution with aqueous fluids. and 8. in a formulation problem where it might be necessary to increase the solubility of a drug 500-fold or more. include 1. Oil injections are only administered intramuscularly. 6. Cosolvency has been used as an approach for preparing liquid drug preparations throughout the history of drug formulation. cosolvents may reduce the degradation of the drug by substituting for some or all of the water in the formulation. Non-aqueous Vehicles: Drugs that are insoluble in aqueous systems are often incor-porated in metabolizable oils. The current USP has monographs for 1. Water-immiscible solvents include 1. 2. are another classic example of a liquid dosage form containing a cosolvent. Although the oils used for injections are of vegetable origin. A common example of a class of formulation containing cosolvents is the elixir. 3. 3. The primary disadvantages of cosolvency include the potential for biological effects and the potential for drugs that have been solubilized using cosolvents to precipitate
Prof. Propylene glycol. and vitamins are incorporated in vegetable oils such as peanut. If a drug is susceptible to hydrolytic degradation. This would be significant. hormones. Isopropyl myristate. 5. In addition. Dioxolanes. and 5. Sterile WFI.SOLVENT / VEHICLE
SOLVENT / VEHICLE Water: The vast majority of injectable products and oral liquid formulations are aqueous solutions because of the physiological compatibility of water with body tissues. and its hydrogen-bonding potential facili-tates the solution of alcohols.
Page. then. the high dielectric constant of water makes it possible to dissolve ionizable electrolytes. for example. In many cases. cosolvents may be effective by one or two mechanisms. Polyethylene glycol 400 and 600.
increase the solubility of poorly water-soluble substances or to enhance the chemical stability of a drug. a cosolvent may enhance the stability of a drug by providing a less suitable environment for the transition state of the reactants. especially with the increasing structural complexity of new therapeutic agents. The biological effects of a cosolvent that may limit or eliminate its use in drug formulations include their general toxicity. N-q3-hydroxyethyl)-lactamide. Purified Water. or sensitizing. Bacteriostatic WFI. Butylene glycol. it is also commonly referred to as solvent blending. Sterile Water for Irrigation. and topical use remains high. Dept. Tinctures. and that are usually used in combination with water as the vehicle. and fixed oils. because some patients have exhibited allergic re-sponses to certain vegetable oils. 2. hydroalcoholic solution intended for oral use. which generally contain even higher amounts of alcohol. Reza-ul Jalil. Steroids. precipitation of drug upon dilution with aqueous media or during injection or application to mucous membranes must always be considered in deciding if a co-solvent can be used as a vehicle for poorly water-soluble drugs. propylene glycol. Water for Injec-tion (WFI). There are strict speci-fications for the vegetable oils used in manufacturing intramuscular injections. These solvents have been reviewed elsewhere and the reader is referred to this review for further details. corn. cosolvency can increase the solubility of a non-polar drug up to several orders of magnitude above the aqueous solubility. Certain drugs of botanic origin were known to be poorly soluble in water and required formulation in water– ethanol mixtures in order to deliver an adequate dose of drug in a small volume of preparation. When used as a method for increasing the chemical stability of a drug. sesame. target organ toxicity. The most frequently used nonaqueous solvents are polyethylene glycol. Solvents that are miscible with water. they should not be subjected to conditions above room tempera-ture for extended periods of time.19
. 4. Glycerin. Additionally. 2. A non-aqueous solvent must be selected with great care for it must not be irritating. Tech. Alternatively. of Pharma. which by definition is a sweetened. toxic. Fixed oils. Benzyl benzoate. and it must not exert an adverse effect on the ingredients of the formulation. olive. 4. and cottonseed. parenteral. Storage of these preparations is important if stability is to be maintained.
improve spreading. Ampholytic surfactants (also called zwitterionic surfactants). DU.solubilizers for poorly soluble drugs-Miceller solubilization Suspensions.Lyposome. N-Dimethylbetaine. as well as benzalkonium chloride.as base. cetomacrogol). at low concentrations. Anionic surfactants. Examples of pharmaceutical importance include polyoxy ethylated glycolmonoethers (e. Surfactant classification
3. the sulfobetaines).emulsifying agents. where the hydrophile carries no charge but derives its water solubility from highly polar groups such as hydroxyl or polyoxyethylene (OCH2CH2O–) groups. and sodium lauryl sulphate. such as carboxyl (RCOO_). of Pharma. Solid dosage forms. both a negative and a positive charge.. (e. Nonionic surfactants.alkylbenzyl dimethyl ammonium Chlorides. The four main groups of surfactants are defined as follows: 1. sorbitan esters (Spans) and polysorbates (Tweens).20
. Examples of pharmaceutical importance include N-Dodecyl-N. Preservatives. Examples of pharmaceutical importance include potassium laurate.g. where the hydrophilic group carries a negative charge. Niosomes. 2. Tech.wettening agents for hydrophobic drugs Emulsions. sulphonate (RSO3_) or sulphate (ROSO3_).improvement of coating solution spredability Drug delivery.
Page. adsorb onto the surfaces or interfaces of a system and alter the surface or interfacial free energy and the surface or interfacial tension. possessing both polar (hydrophilic) and non-polar (hydrophobic) regions in the same molecule. or can potentially contain. where the hydrophilic group carries a positive charge (e. Applicatons of surfactants
Liquid dosage forms. Aerosols– wetting agents
Surfactant molecules may be classified based on the nature of the hydrophilic group within the molecule.some cationinc surfactants act as preservative. dodecyl and hexa decyl trimethyl ammonium bromides.. Surface-active agents have a characteristic structure. Reza-ul Jalil. a mixture consisting mainly of tetradecyl. where the molecule contains. Micro-emulsions Topical ointment. 4.. Examples of pharmaceutical importance include cetrimide.
SURFACTANTS IN PHARMACEUTICAL PRODUCTS
Surfactants in Pharmaceutical Products Surface-active agents (surfactants) are substances which. a mixture of
• • • • • • •
Prof.g.solubility enhancement or dissolution improvement of poorly soluble drugs Tablet coating. Dept. Thus surfactants are said to be amphipathic in nature. Cationic surfactants.g. quaternary ammonium halide.
1.6 0. To function in this manner. The buffer should permit acceptable flavoring and coloring of the product.005 0. For instance.22 1.1 1. and the pH dependence of solubility is frequently measured using buffered systems.0 0. preformulation scientists routinely use buffer systems to set the pH of a medium in which they intend to perform experimentation. 2.71 0. or during the period associated with its administration. A buffer can be defined as a solution that maintains an approximately equal pH value even if small amounts of acidic or basic substances are added. The buffer should have little or no deleterious effect on the stability of the final product. Selection criteria for buffering agents:
Acetic acid Adipic acid Benzoic acid and sodium benzoate Citric acid Lactic acid Maleic acid Potassium phosphate Sodium phosphate monobasic Sodium phosphate dibasic Sodium acetate Sodium bicarbonate Sodium carbonate Sodium citrate Sodium tartrate Tartaric acid
Concentration range (%) 0.
Prof. 4. The properties that enable buffering agents to function as such is derived from their qualities as weak acids or bases. The buffer must be biologically safe for the intended use.21
. Reza-ul Jalil.5 0. and such information is routinely gathered during the preformulation stage of development. the pH stability profile of a drug substance is routinely obtained through the use of buffers.0 1. formulators commonly include a buffer system to ensure the stability of the drug substance either during the shelf life of the product. 3.7 0. Buffers in pharmaceutical systems It is well known that the stability of many active pharmaceutical substances can be strongly dependent on the degree of acidity or basicity to which they are exposed. and that a change in pH can cause significant changes in the rate of degradation reactions. the possibility that the buffer system itself may influence or alter the results must be considered in these studies.06 4.8 0. a buffer solution will necessarily contain either an acid and its conjugate base. The buffer must have adequate capacity in the desired pH range.0 5. Dept.Buffers
Buffers It is well known that many drugs are unstable when exposed to certain acidic or basic conditions.
Page.2 0. When such instabilities are identified. Tech. or a base and its conjugate acid. of Pharma. In addition. one tool of the formulation sciences is to include a buffering agent (or agents) in the dosage form with the hope that such excipients will impart sufficient stability to enable the formulation. For such compounds.1 1. DU. However. and have their roots in their respective ionic equilibria.
Reza-ul Jalil. outside the granules) before tablet compression. disintegrants).g..g. Furthermore.g.. of Pharma. binders and lubricants. the level of excipient use is usually limited to only a few percent and some lubricants will be required at <1%. and mechanisms of action of various excipients for tablet and capsule production have been discussed at length in other articles in this encyclopedia. some of these tableting excipients may possess
>1 function that may be similar (e. the sequence of adding the excipients during tablet production depends on the function of the excipient. lubricants. which may be present in large quantity..EXCIPIENTS IN TABLETS AND CAPSULES
For tablets and capsules.. and antiadherents are specific for making tablets. inside the granules).
Prof. glidants) and for the formulation (e.e. DU. Details of the types. The types and functions of excipients for tablet production are summarized in Table 1. may hinder the disintegration action of the disintegrants. In addition. excipients are needed both for the facilitation of the tableting and capsule-filling process (e.. uses. Dept.g.
Page. Although binders. For example.e. disintegrants may be added before granulation (i. talc as lubricant and glidant) or opposite (e.. It is worth noting that some of these tableting excipients may exert effects in opposition to each other.22
. Tech. Whereas the diluents and the binders are to be mixed with the active ingredient early on for making granules. starch as binder and disintegrant) to each other. because of their respective bonding and waterproofing properties. other excipients in Table 1 are also used in capsule production for reasons similar to those for tablets. and/or during the lubrication step (i. Except for diluents.
Page. pH-dependent solubility (controlled release). Modern or advanced pharmaceutical dosage forms utilize polymers for drug protection. controlled release of a given drug. Table 20–3 provides a list of polymers with their applications in pharmaceutical and biomedical industries. From the structural prospective.
Major application of polymers in current pharmaceutical field is for controlled drug release. the desirable polymer properties in pharmaceutical applications are film forming (coating). four. pharmaceutical polymers can be classified as water-soluble and water-insoluble (oilsoluble or organic soluble). or five monomers are attached to each other. polyvinyl pyrrolidone. 20–1). among them polyethylene glycol. polymers are used as tablet binders to bind the excipients of the tablet.POLYMERS
A monomer is a small molecule that combines with other molecules of the same or different types to form a polymer. whereas ethyl cellulose and a group of cellulose esters such as cellulose acetate butyrate or phthalate are organic soluble. and barrier properties (protection and packaging). Products containing more than 200 monomers are simply called a polymer (Fig. polyethylene oxide. The synthetic water-soluble polymers have also found extensive applications in pharmaceutical industries. increase drug bioavailability. the product is known as a dimer. This requires that the polymers have unique properties that are not offered by polymers intended for general applications. In general. Tech. or pentamer. taste masking. polyethylene glycol vinyl alcohol polymers. such as tablet manufacturing. and so on and so forth. An oligomer contains from 30 to 100 monomeric units. targeted delivery.
Prof. The cellulose ethers with methyl and hydroxypropyl substitutions are water-soluble. Apart from solid dosage forms. gelling (controlled release). If two. Hydrocolloid gums are also used when solubility in water is desirable. polymers are generally used as implants and are expected to perform longterm service. tetramer. DU. three. polymers have found application in liquid dosage forms as rheology modifiers. monomers are generally classified as olefinic (containing double bond) and functional (containing reactive functional groups) for which different polymerization methods are utilized. Reza-ul Jalil. which will be discussed in detail in the following sections. trimer. From the solubility standpoint. In the biomedical area. and polyacrylate or polymethacrylate esters containing anionic and cationic functionalities are wellestablished. Since drawing a complete structure of a polymer is almost impossible. Dept. solubility in organic solvents (taste masking). respectively. adhesion (binding).23
. They are used to control the viscosity of an aqueous solution or to stabilize suspensions or even for the granulation step in preparation of solid dosage forms. In a traditional pharmaceutics area. the structure of a polymer is displayed by showing the repeating unit (the monomer residue) and an “n” number that shows how many monomers are participating in the reaction. of Pharma. thickening (rheology modifier).
Page. DU. of Pharma. Reza-ul Jalil.PHARMACEUTICAL EXCIPIENTS
Prof. Tech. Dept.
Page. of Pharma.25
. Reza-ul Jalil. Tech.PHARMACEUTICAL EXCIPIENTS
Prof. Dept. DU.
subsequently. but cannot contain any nature-identical or artificial flavouring substances. suffered from considerable imprecision in definition. the story is different. the field has remained relatively unchanged. which are chemically identical to flavouring substances naturally present in products intended for human consumption. but incomplete.
Prof. . except for the advent of new semi-synthetic flavoring agents with improved stability. . DU. In the analytical arena.Sweet. Taste partly depends on the ions which are produced in the mouth. whether or not the product is processed. . Tech. the blend of taste and smell sensations evoked by a substance in the mouth. perceived principally by the senses of taste and smell. quality of something that affects the sense of taste. . It is usually associated with the pleasure of savoring food or beverages and has. Webster’s New Collegiate Dictionary defines flavor as the ‘‘ . Thus.FLAVORS AND FLAVOR MODIFIERS
Flavors and Flavor Modifiers
The use of flavors and flavor modifiers to improve the taste and aroma of foods and pharmaceuticals is an art that dates back several centuries. and ingestion of a food. therefore. They cannot contain any artificial flavouring substances.” Flavor is the complex effect of three components: taste. the practice is still the same today and. Reza-ul Jalil. bitter. “Flavor is the sensation produced by a material taken in the mouth. acceptance. Nature-identical flavouring substances: Natureidentical substances means flavouring substances that are obtained by synthesis or isolated through chemical processes. by physical.26
.’’ This definition is correct. Flavor is a sensation with multidimensional components involving subjective and objective perceptions. but psychologists have demonstrated that sight (color) and sound also play a definite role when certain reflexes become conditioned through custom and association of sense perceptions. and temperature receptors in the mouth. odor. Flavor also denotes the sum of the characteristics of the material which produces that sensation.
3. microbiological or enzymatic processes. Artificial flavouring substances: Artificial flavouring substances means flavouring substances not identified in a natural product intended for human consumption. in the classic experiments of Pavlov demonstrating "conditiond
2. DEFINITION OF FLAVOR The sensory perceptions are both qualitative as well as quantitative and.”
CLASSIFICATION OF FLAVORING AGENTS Natural flavouring substances: Natural flavouring substances means flavouring substances obtained from plant or animal raw materials. and should be redefined to include feeling factors. of Pharma. and also by the general pain. and feeling factors. can be measured. . They can be either used in their natural state or processed for human consumption. Dept. 1. “ Flavor is one of the three main sensory properties which are decisive in the selection. TASTE The four primary taste.
Page. sour and salineappea4r to be the result of partly of physicochemical and partly of psychological action. tactile. In large measure.
Odor: The odor component of flavor is due to conscious or subconscious reactions to volatile substances. contribute to the overall flavor of foods. poly halogeneted aliphatic compounds. to rupture oil cells in the rind. Tech. or natural and artificial (N&A) by combining the all natural and synthetic flavors. DU. Pharmaceutical flavors are available as liquids (e. waxy residues). pepper bite. spraydried. This process improves solubility and enhances flavor intensity. the ringing of a bell or the showing circle of light caused the gastric juices of a dog to follow although no food was placed before it.g. solids (e.. softness or hardness as in candy). etc.. Citrus essential oils are almost exclusively obtained by this method. NaCl. sorbitol. Saltinesssimultaneos presence of anions and cations. resins. There are many varieties of odorants. there is evidence that odor may involve specific receptor interactions. Characteristics of acids. bitter. Feeling Factors: ‘‘Mouth feel’’ factors are critical in flavor perception. essential oils. FLAVOR SELECTION IN PHARMACEUTICAL PREPARATIONS A number of criteria are used to select flavors during formulation. They are available both as oily (e.g. Taste consists of four primary sensations: sweet. Their texture is generally dependent on the solvent within which they are prepared. tannins. Correspondingly. on the drug substance and the physical form of the product. Dept. Reza-ul Jalil. sour. alum. phenol and lactons.g.Flavor types
Cherry Pineapple Peach apricot Apple Banana Strawberry Raspberry Grape Plum Black currant Orange Vanilla Mango Lemon Honey Coconut Butter Cocoa Milk Cinnamon Cardamon Clove Anise Mint Pepermint Garlic Zinger
head cold.g KBr. The oil is collected by draining and centrifuging. and salty. FLAVORING AGENTS
reflexs". and dried lemon fluid extract). e. Correlation of chemical structure with taste: Sour taste. or mechanically. Sesquiterpeneless oils are more soluble than terpeneless oils because of the removal of head and tail fractions (e. soft extracts. such as crunch after biting into a crisp stick of celery or an apple. tinctures. it may be shown that food could be rendered tasteless. Tinctures are obtained by maceration or percolation of specific herbs and spices in alcohol. The tenth and twelfth cranial nerves participate in this sensory reaction. Oils and juices are obtained from plant sources by expression. Thoroughly washed unripe citrus fruits are cold pressed manually. steam. and fractional or molecular distillation are often used for their manufacture. Examples include astringency. when selecting a flavor system.. These sensations are elicited by the tongue and interpreted by the brain.. Liquid flavors are by far the most widely used because they diffuse readily into the substrate. and distillates)... crystalline vanillin. artificial. as is often experienced by people suffering from the effects of a PHARMACEUTICAL EXCIPIENTS
Flavoring agents may be classified as natural.high molecular weight salts are bitter. essential oils) or non-oily liquids. resinous materials. but salty sensations are usually detected at both the tip and at the sides of the tongue. Sensations. For this reason.hydrogen ions.g. Sour sensations occur at the sides of the tongue. Sweet sensations are most easily detected at the tip of the tongue. Specific requirements for balance and fullness are dependent. eg.
. and sesquiterpenes from the distillate. many drugs. colors. whereas bitter ones are most readily detected at the back of the tongue. and texture (e. freeze-dried cinnamon powders. Most common sesquiterpeneless oils used in the pharmaceutical industry include oil of orange and oil of lemon. Essential oils boil at elevated temperatures. and pastes (e. glycerin. Fractional distillation removes traces of water. By closing the nostrils while eating a mouthful of some flavored substance and immediately following this with another mouthful with the nostrils open. there are four different kinds of taste buds. Different flavor concentrations produce highly subjective sensations. These mouth feel factors are also important in improving the organoleptic qualities of pharmaceuticals. but many cannot be directly distilled without decomposition. Certain areas of the tongue respond more readily to specific tastes than others.27
Bitterness. Yet. the Page. sugars. fluid extracts. and "amino acids. Alkalis both base and salt. but their role is limited.g. suggesting that structural properties of odorants may be important in eliciting specific odor sensations. but a universally accepted structure–activity relationship of these has not been established. menthol cooling.g. taste buds react to soluble substances. of Pharma. terpenes. The resulting sensations are transmitted to the brain by the ninth cranial (glossopharyngeal) nerve. During ingestion. and so-called concretes. Sweetdue to poly hydroxy compounds. in part. which are brittle on the outside and soft on the inside). glucose. without which most foods would be lacking in taste appeal. Fluid extracts may contain a single ingredient or a variety of compounded ingredients. Manual operation is labor intensive and has been replaced by machines.
Maltitol and sorbitol are often used. increasing overall flavor quality. The artificial sweetener saccharin is widely used in foods and pharmaceuticals. Flavor Enhancers and Potentiators Flavor enhancers are used universally in the food and pharmaceutical industries. Taste-Masking Agents
The most commonly used sweeteners are sucrose. glucose. Some of these are product texture (e.’’ that is. malic. which have been used with some success.. base vehicle or substrate. are about 30_ as sweet as sugar. sorbitol.g. It is sweet at very low concentrations (equivalent to about 5–10% sugar) but bitter at higher concentrations.g. of Pharma. for example. it has a negative heat of solution. solid or liquid). many fruit syrups are relatively stable in pharmaceuticals if formulated with antimicrobial preservative agents. In many other PHARMACEUTICAL EXCIPIENTS
The flavoring industry has many proprietary products purported to have excellent taste-masking properties. Approximately 20% of the population are ‘‘saccharin sensitive. Vehicle components within which the drug is presented have a significant bearing on the performance of the flavor system. carboxylic acids (e. Table 6 lists the relative intensities of other sweeteners. Equal. and in foods such as "no sugar added" ice cream. viscosity of formulation. List of sugar substitutes The three primary compounds used as sugar substitutes in the United States are saccharin (e... which is effectively enhanced by salt. Mannitol is used more often in tablet manufacture. Other acidic agents.Altern). their sweet–bitter profiles are concentration dependent. MSG has limited use in pharmaceuticals because it is not a sweetener. Cyclamates were banned in the 1970s because of carcinogenic concerns. cherry. Sweet'N Low). Common salt provides similar effects at its taste threshold level in liquid pharmaceuticals. glucose. It is approximately 350_ as sweet as sugar. Citric acid is most frequently used to enhance taste performance of both liquid and solid pharmaceutical products.28
. the sweetener is perhaps the most relevant. such as malic and tartaric acids. This so-called ‘‘miracle berry’’ contains a glycoprotein that transiently and selectively binds to bitter taste buds. Dept. monosodium glutamate—MSG). requires an extensive evaluation of a number of organoleptic qualities. cocoa. Using sucrose (sugar) as a standard. aspartame (e. Sweeteners
countries xylitol. Aspartame does not have a significant bitter aftertaste when compared to saccharin and has gained in popularity. fructose. Notable specific examples to consider are: _ Immediate flavor identity from the formulation as it is ingested. attempts to isolate the compound for commercial exploitation have been unsuccessful.g. NutraSweet) and sucralose (e.. DU. as well as a variety of foods.. _ Absence of ‘‘off’’ notes in the mouth and a mild transient aftertaste during ingestion of the product. In oral liquids. Of the many tastes that must be masked in pharmaceuticals. and tartaric). common salt (NaCl). The artificial sweeteners. solutions of relatively low concentrations are often no longer sweet to the saccharin -sensitive person. and sucrose have limited use in solid dosage forms (e. thus. there are a number of natural and artificial flavors that can be generally described to possess similar taste-masking effects.g. cyclamate and aspartame. bitterness is most often encountered.compounding pharmacist must take into account several variables upon which a desired response would depend. peppers) are most often employed. citric. A tropical fruit has been used for centuries in central Africa to mask the bitter taste of native beers. cyclamate and the herbal sweetener stevia are used extensively. has a delicate bland flavor. Yet. which complements flavor quality. Due to stability challenges. citric acid.g. water content.g.g. Besides being less hygroscopic. to mask it completely is difficult.. and taste of the subject drug. Sugar. amino acids. and glycerin. Glycerin. sorbitol. Of these. Vanilla. Erythritol is gaining momentum as a replacement for these other sugar alcohols in foods as it is much less likely to produce gastrointestinal distress when consumed in large amounts. By the third or fourth tasting. wild
Prof. frequently in toothpaste. tablets) because the materials are hygroscopic. The selection of a flavor system. which have.. Tech. they perceive saccharin to be bitter even at low concentrations. with 100 units of sweetness. chewable tablets containing mannitol have a pleasant cooling sweet taste. Splenda. saccharin becomes less sweet and increasingly bitter. some amino acid derivatives (e. mouth wash.
Page. but like saccharin. orange. and spices (e. subsequently. _ Compatible mouth feel factors and rapid development of a fully blended flavor in the mouth during ingestion of the product.g. Yet. been shown to be overstated. are also used for flavor enhancement. Although extremely effective with proteins and vegetables.. For this reason. these acids contribute unique and complex organoleptic effects. Syrups of cinnamon. Upon repeated tasting. Reza-ul Jalil.
500× sweetness (by weight). E954. E952.000× sweetness (by weight). FDA Banned 1950 Prof.0× sweetness (by weight). Dept.9× sweetness (by weight). a steviol glycoside — protein. Abbott. does not taste sweet by itself.g.2× sweetness (by food energy).65× sweetness (by weight).000× sweetness (by weight). a tropical fruit. E422 — 0. Tate & Lyle. The extent to which taste-masking may be achieved is not usually predictable due to complex interactions of other flavor elements in these products.9–1. orange. 0.05× energy density of sucrose — 50× sweetness (by weight) — 0.5× energy density. Metallic tastes in oral liquid products (e.001 to about 0.9× sweetness (by weight).. mainly containing rebaudioside A. Pending FDA Approval — 30× sweetness (by weight).7× sweetness (by weight). followed by raspberry syrup.7× sweetness (by food energy).000× sweetness (by weight). E965 — 0. 3.29
. Reza-ul Jalil. E951. 0.4× energy density. 0. E967
— naturally-occurring sweetener isolated from the plant Sclerochiton ilicifolius — 250× sweetness (by weight) . Splenda. E957 — protein. 800× sweetness of sucrose (by weight) — protein.4× sweetness (by food energy).55× sweetness (by food energy). NutraSweet. The degree to which bitterness may be masked by these agents ranks in a descending order: cocoa syrup is most effective.5×–1. E955. 2.2× sweetness (by food energy). 0.65× energy density. Sour substances containing hydrochloric acid are most effectively neutralized with raspberry and other fruit syrups.g. Gurana flavor is used at concentrations ranging from 0. FDA Approved 1981 — 8.8× sweetness (by food energy). cinnamon. 100× sweetness (by weight)
Monellin Pentadin Miraculin Thaumatin Brazzein Curculin Mabinlin
Artificial sugar substitutes Sucralose Saccharin Aspartame Neotame Salt of aspartame-acesulfame Acesulfame potassium Glucin Neohesperidin dihydrochalcone Alitame Cyclamate Dulcin PHARMACEUTICAL EXCIPIENTS
— 600× sweetness (by weight). FDA Approved 1998 — 300× sweetness (by weight). chewable tablets and granules). licorice.cherry. Nutrinova. Page. 2.5% and may be useful in solid products as well (e. 1. Sour and metallic tastes in pharmaceuticals also can be reasonably masked. E966 — 0.45–0. compound sarsaparilla. 1.extracts known as rebiana.6× sweetness (by weight). 0. 14× sweetness of sucrose (by food energy).3× sweetness (by food energy).000× sweetness (by weight).9× sweetness (by food energy). E953 — 0. cherry. Pfizer.
Natural sugar substitutes SUCROSE — 0. Twinsweet. 0.6× sweetness (by weight).92× sweetness (by weight). E950.38× energy density — 1. FDA Approved 1958 — 160–200× sweetness (by weight).7× sweetness (by food energy). 500× sweetness (by weight) — protein. E959 — 2. Truvia. 550× sweetness (by weight) — protein. 0. NutraSweet.4× sweetness (by weight). FDA Approved 1988 — 300× sweetness (by weight) — 1. iron) are usually masked by extracts of gurana. PureVia. citric acid. DU. FDA Approved 2002 — 350× sweetness (by weight).5× energy density. E420 Sorbitol Glycerol Mannitol Erythritol Glycyrrhizin Hydrogenated starch hydrolysates Inulin Isomalt Lactitol Maltitol Tagatose Xylitol Plant extracts Monatin Stevia — 0.4–0. 0. raspberry. Tech. 0. the sweetening ingredient in serendipity berries — protein.525× energy density. FDA Banned 1969 — 250× sweetness (by weight).075× energy density. E962 — 200× sweetness (by weight). E421 — 0.75× energy density
— 0. and wild cherry. 0. 0. 0.6× energy density. of Pharma. 1. or glycyrrhiza elixir can be used to effectively mask salty and bitter tastes in a number of drug products. but modifies taste receptors to make sour things taste sweet temporarily — protein. 1..
aromatic elixir. Kaltame.5× sweetness (by weight). 0. 0.
Reza-ul Jalil. Monobasic-Buffering Agent Boric Acid-Buffering Agent Diethanolamine-Buffering Agent Disodium Edetate-Chelating Agent Edetic Acid-Chelating Agent Pentetic Acid-Chelating Agent Shellac-Coating Agent Zein-Coating Agent Iron Oxides-Color Titanium Dioxide-Color-Pigment Cyclodextrins-Complexing Agent Hydroxypropyl Betadex-Complexing Agent Sulfobutylether b-Cyclodextrin-Complexing Agent Calcium Chloride-Desiccant Chloroxylenol-Disinfectants Lactose. Anionic Emulsifying-Emulsifying Agent
PHARMACEUTICAL EXCIPIENTS Prof. Inhalation-Dpi-Diluent Potassium Bicarbonate-Effervescent-Base Sodium Bicarbonate-Effervescent-Base Isopropyl Myristate-Emollient Isopropyl Palmitate-Emollient Mineral Oil-Emollient Mineral Oil. Glacial-Buffering Agent Adipic Acid-Buffering Agent Ammonia Solution-Buffering Agent Calcium Hydroxide-Buffering Agent Citric Acid Monohydrate-Buffering Agent Lactic Acid-Buffering Agent Maleic Acid-Buffering Agent Meglumine-Buffering Agent Monoethanolamine-Buffering Agent Potassium Citrate-Buffering Agent Potassium Hydroxide-Buffering Agent Sodium Carbonate-Buffering Agent Sodium Citrate Dihydrate-Buffering Agent Sodium Lactate-Buffering Agent Sodium Phosphate.EXCIPIENT-Classification
Ammonium Chloride-Acidulant Fumaric Acid-Acidulant Hydrochloric Acid-Acidulant Malic Acid-Acidulant Phosphoric Acid-Acidulant Sulfuric Acid-Acidulant Tartaric Acid-Acidulant Aluminum Hydroxide Adjuvant-Adsorbant Aluminum Oxide-Adsorbant Aluminum Phosphate Adjuvant-Adsorbant Attapulgite-Adsorbant Colloidal Silicon Dioxide-Adsorbant Hydrophobic Colloidal Silica-Adsorbant Magnesium Oxide-Adsorbant Dimethicone-Antifoaming Agent Simethicone-Antifoaming Agent Alpha Tocopherol-Antioxidant Ascorbic Acid-Antioxidant Ascorbyl Palmitate-Antioxidant Butylated Hydroxyanisole-Antioxidant Butylated Hydroxytoluene-Antioxidant Butylparaben-Antioxidant Erythorbic Acid-Antioxidant Monothioglycerol-Antioxidant Potassium Metabisulfite-Antioxidant Propyl Gallate-Antioxidant Sodium Ascorbate-Antioxidant Sodium Formaldehyde Sulfoxylate-Antioxidant Sodium Metabisulfite-Antioxidant Sodium Sulfite-Antioxidant Sodium Thiosulfate-Antioxidant Sulfur Dioxide-Antioxidant Potassium Alum-Astringent Sodium Borate-Astringent Denatonium Benzoate-Bittering Agent Sucrose Octaacetate-Bittering Agent Acetic Acid. Page. Light-Emollient Lecithin-Emulsifier Cholesterol-Emulsifying Agent Mineral Oil and Lanolin Alcohols-Emulsifying Agent Octyldodecanol-Emulsifying Agent Polyoxylglycerides-Emulsifying Agent Triethanolamine-Emulsifying Agent Vitamin E Polyethylene Glycol Succinate-Emulsifying Agent Wax. DU.30
. Dept. of Pharma. Tech. Dibasic-Buffering Agent Sodium Phosphate.
Yellow-Polishing Agent Aliphatic Polyesters-Polymer Carbomer-Polymer Cellulose Acetate-Polymer Cellulose Acetate Phthalate-Polymer Dextrin-Polymer Ethylcellulose-Polymer Ethylene Vinyl Acetate-Polymer Gelatin-Polymer Hydroxyethyl Cellulose-Polymer Hydroxyethylmethyl Cellulose-Polymer Hydroxypropyl Cellulose-Polymer Hydroxypropyl Cellulose. Nonionic Emulsifying-Emulsifying Agent Ethylene Glycol Stearates-Emulsion Stabilizer Glyceryl Behenate-Emulsion Stabilizer Glyceryl Monooleate-Emulsion Stabilizer Glyceryl Monostearate-Emulsion Stabilizer Glyceryl Palmitostearate-Emulsion Stabilizer Ethyl Maltol-Flavoring Agent Ethyl Vanillin-Flavoring Agent Isomalt-Flavoring Agent Leucine-Flavoring Agent Maltol-Flavoring Agent Menthol-Flavoring Agent Methionine-Flavoring Agent Monosodium Glutamate-Flavoring Agent Vanillin-Flavoring Agent Carbon Dioxide-Gas Nitrogen-Gas Acacia-Hydrocolloid Alginic Acid-Hydrocolloid Ammonium Alginate-Hydrocolloid Calcium Alginate-Hydrocolloid Carrageenan-Hydrocolloid Chitosan-Hydrocolloid Guar Gum-Hydrocolloid Pectin-Hydrocolloid Potassium Alginate-Hydrocolloid Sodium Acetate-Hydrocolloid Sodium Alginate-Hydrocolloid Tragacanth-Hydrocolloid Xanthan Gum-Hydrocolloid Polacrilin Potassium-Ionexchange Resin Almond Oil-Oily Vehicle Canola Oil-Oily Vehicle Castor Oil-Oily Vehicle Coconut Oil-Oily Vehicle Corn Oil-Oily Vehicle Cottonseed Oil-Oily Vehicle Ethyl Oleate-Oily Vehicle Medium-chain Triglycerides-Oily Vehicle Oleyl Alcohol-Oily Vehicle Olive Oil-Oily Vehicle Palmitic Acid-Oily Vehicle Peanut Oil-Oily Vehicle Safflower Oil-Oily Vehicle
Sesame Oil-Oily Vehicle Soybean Oil-Oily Vehicle Sunflower Oil-Oily Vehicle Castor Oil. White-Polishing Agent Wax. of Pharma. Reza-ul Jalil. Page. Carnauba-Polishing Agent Wax. DU. Low-substituted-Polymer Hydroxypropyl Starch-Polymer Hypromellose-Polymer Hypromellose Acetate Succinate-Polymer Hypromellose Phthalate-Polymer Methylcellulose-Polymer Poloxamer-Polymer
. Hydrous-Ointment Base Paraffin-Ointment Base Petrolatum-Ointment Base Petrolatum and Lanolin Alcohols-Ointment Base Sodium Hydroxide-Ph ADJUSTMENT Acetyltributyl Citrate-Plasticizer Acetyltriethyl Citrate-Plasticizer Dibutyl Phthalate-Plasticizer Dibutyl Sebacate-Plasticizer Diethyl Phthalate-Plasticizer Dimethyl Phthalate-Plasticizer Triacetin-Plasticizer Tributyl Citrate-Plasticizer Triethyl Citrate-Plasticizer Wax. Tech. Hydrogenated-Ointment Base Ceresin-Ointment Base Cetostearyl Alcohol-Ointment Base Cetyl Alcohol-Ointment Base Lanolin-Ointment Base Lanolin Alcohols-Ointment Base Lanolin.Wax.
Reza-ul Jalil. Cetyl Esters-Stiffening Agent Wax. Dept. of Pharma. Microcrystalline-Stiffening Agent Suppository Bases. Hard Fat-Suppository Base Docusate Sodium-Surfactant Macrogol 15 Hydroxystearate-Surfactant Phospholipids-Surfactant Polyoxyethylene Alkyl Ethers-Surfactant Polyoxyethylene Castor Oil Derivatives-Surfactant Polyoxyethylene Sorbitan Fatty Acid Esters-Surfactant Polyoxyethylene Stearates-Surfactant Sodium Lauryl Sulfate-Surfactant Sorbitan Esters (Sorbitan Fatty Acid Esters)-Surfactant Bentonite-Suspending Agent
Prof.Poly(DL-Lactic Acid)-Polymer Poly(methyl vinyl ether/maleic anhydride)-Polymer Polycarbophil-Polymer Polydextrose-Polymer Polyethylene Glycol-Polymer Polyethylene Oxide-Polymer Polymethacrylates-Polymer Polyvinyl Acetate Phthalate-Polymer Polyvinyl Alcohol-Polymer Povidone-Polymer Carboxymethylcellulose Sodium-Polymer Carboxymethylcellulose Calcium-Polymer Copovidone-Polymer Potassium Sorbate-Preservative Benzalkonium Chloride-Preservative Benzethonium Chloride-Preservative Benzoic Acid-Preservative Benzyl Alcohol-Preservative Benzyl Benzoate-Preservative Bronopol-Preservative Cetrimide-Preservative Cetylpyridinium Chloride-Preservative Chlorhexidine-Preservative Chlorobutanol-Preservative Chlorocresol-Preservative Cresol-Preservative Ethylparaben-Preservative Hexetidine-Preservative Imidurea-Preservative Methylparaben-Preservative Phenol-Preservative Phenoxyethanol-Preservative Phenylethyl Alcohol-Preservative Phenylmercuric Acetate-Preservative Phenylmercuric Borate-Preservative Phenylmercuric Nitrate-Preservative Potassium Benzoate-Preservative Propionic Acid-Preservative Propylparaben-Preservative Propylparaben Sodium-Preservative Sodium Benzoate-Preservative Sodium Propionate-Preservative Sorbic Acid-Preservative Thimerosal-Preservative
Thymol-Preservative Chlorodifluoroethane (HCFC)-Propellant Chlorofluorocarbons (CFC)-Propellant Difluoroethane (HFC)-Propellant Dimethyl Ether-Propellant Heptafluoropropane (HFC)-Propellant Hydrocarbons (HC)-Propellant Nitrous Oxide-Propellant Tetrafluoroethane (HFC)-Propellant Acetone-Solvent Alcohol-Solvent Butylene Glycol-Solvent Cyclomethicone-Solvent Dimethyl Sulfoxide-Solvent Dimethylacetamide-Solvent Ethyl Acetate-Solvent Ethyl Lactate-Solvent Glycerin-Solvent Glycofurol-Solvent Isopropyl Alcohol-Solvent Propylene Carbonate-Solvent Propylene Glycol-Solvent Pyrrolidone-Solvent Triolein-Solvent Albumin-Stabilizer Calcium Acetate-Stabilizer Glycine-Stabilizer Raffinose-Stabilizer Trehalose-Stabilizer Zinc Acetate-Stabilizer Stearyl Alcohol-Stiffening Agent Wax. Page. DU.32
Powdered-Tablet Diluent Cellulose. Spray-Dried-Tablet Diluent Magnesium Carbonate-Tablet Diluent Maltodextrin-Tablet Diluent Sodium Starch Glycolate-Tablet Disintegrant Croscarmellose Sodium-Tablet Disintegrant Crospovidone-Tablet Disintegrant Magnesium Silicate-Tablet Glidant Magnesium Trisilicate-Tablet Glidant Talc-Tablet Glidant Calcium Stearate-Tablet Lubricant Starch. Silicified Microcrystalline-Tablet Diluent Starch-Tablet Diluent Starch. Pregelatinized-Tablet Diluent Corn Starch and Pregelatinized Starch-Tablet Diluent Dextrates-Tablet Diluent
Erythritol-Tablet Diluent Inulin-Tablet Diluent Lactose. Dibasic Anhydrous-Tablet Diluent Calcium Phosphate.
Page. Hydrogenated-Tablet Lubricant Zinc Stearate-Tablet Lubricant Magnesium Stearate-Tablet Lubricant Potassium Chloride-Tonicity Contributor Sodium Chloride-Tonicity Contributor Lauric Acid-Transdermal Penetration Enhancer Linoleic Acid-Transdermal Penetration Enhancer Myristic Acid-Transdermal Penetration Enhancer Myristyl Alcohol-Transdermal Penetration Enhancer Oleic Acid-Transdermal Penetration Enhancer Tricaprylin-Transdermal Penetration Enhancer Aluminum Monostearate-Viscosity Imparting For Oil
Prof. Dept. Tech. Microcrystalline-Tablet Diluent Cellulose.33
. Monohydrate-Tablet Diluent Lactose. Dibasic Dihydrate-Tablet Diluent Calcium Phosphate. Sterilizable Maize-Tablet Lubricant Sodium Stearyl Fumarate-Tablet Lubricant Stearic Acid-Tablet Lubricant Vegetable Oil. Anhydrous-Tablet Diluent Lactose. Liquid-Sweetening Agent Lactitol-Sweetening Agent Maltitol-Sweetening Agent Maltitol Solution-Sweetening Agent Maltose-Sweetening Agent Mannitol-Sweetening Agent Neohesperidin Dihydrochalcone-Sweetening Agent Neotame-Sweetening Agent Saccharin-Sweetening Agent Saccharin Sodium-Sweetening Agent Sodium Cyclamate-Sweetening Agent Sorbitol-Sweetening Agent Sucralose-Sweetening Agent Sucrose-Sweetening Agent Sugar.Calcium Silicate-Suspending Agent Ceratonia-Suspending Agent Hectorite-Suspending Agent Kaolin-Suspending Agent Magnesium Aluminum Silicate-Suspending Agent Propylene Glycol Alginate-Suspending Agent Saponite-Suspending Agent Sodium Hyaluronate-Suspending Agent Aspartame-Sweetening Agent Dextrose-Sweetening Agent Fructose-Sweetening Agent Glucose. Confectioner’s-Sweetening Agent Tagatose-Sweetening Agent Thaumatin-Sweetening Agent Xylitol-Sweetening Agent Acesulfame Potassium-Sweetening Agent Alitame-Sweetening Agent Calcium Carbonate-Tablet Diluent Calcium Lactate-Tablet Diluent Calcium Phosphate. of Pharma. DU. Tribasic-Tablet Diluent Calcium Sulfate-Tablet Diluent Cellulose. Reza-ul Jalil.