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Introduction

 Accounts for greatest number of available


Formulations for preparations
Oral Administration 

Accurate and versatile dosage
Good physical and chemical stability
 Competitive unit production costs
Department of Industrial Pharmacy
 Elegant, distinctive appearance
College of Pharmacy, UP Manila
 Potential disadvantages
 Bioavailability problems
 Irritant effects on the gastrointestinal mucosa
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General Considerations

 Need to produce tablets and capsules of


uniform weight
 Feeding constant volumes of homogenous material
 Need to manufacture a unit of sufficient
mechanical strength yet capable of
reproducible breakdown on administration
FORMULATION OF SOLIDS  Control of processing conditions

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Desirable Properties of
API
Raw Materials
API Flavor Antifrictional  Amount and type will influence size and choice of
excipients
Filler Binder Surfactant  Very small doses affect content uniformity and stability
 Crystal habit, Polymorphism
Color Adsorbent Coating Disintegrant  Particle shape
 Effect of processing
 Uniform dispersion within the mixture  Compaction properties
 Brittle, crystalline drugs
 Minimal tendency for component segregation  Strain index, Brittle fracture index, Bonding index
 Flow characteristics  Density
 Compressibility  Moisture level
 Surface area
 Multi--functional
Multi
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Filler/Diluent
Filler/Diluent Binder
compactibility flowability solubility disintegration hygroscopicity lubricity stability Binder/ granulating fluid % strength Remarks
Dextrose 3 2 4 2 1 2 3 Water Easily hydratable material

Spray-dried
Spray- 3 5 4 3 1 2 4 alcohol Easily hydratable material
lactose
Fast-flo
Fast- 4 4 4 4 1 2 4 Acacia mucilage 10-
10-20 Hard, friable granules
lactose
Tragacanth mucilage 10-
10-20 Hard, friable granules
Anhydrous 2 3 4 4 5 2 4
lactose Gelatin solutions 10-
10-20 Gels when cold; strong adhesive for
Sucrose 4 3 5 4 4 1 4 lozenges; not for warm moist climates
Starch 2 1 0 4 3 3 3 Starch mucilage 5-10 One of the best; use warm
Starch 1500 3 2 2 4 3 2 4 Glucose syrups 25-
25-50 Strong adhesive; tablets may soften in high
humidity
Dicalcium 3 4 1 2 1 2 5
phosphate Sucrose syrups 65-
65-85 Strong adhesive; tablets may soften in high
Encompress 3 5 0 3 1 1 5 humidity
PVP 3-15 Differing MW grades give varying results
Avicel 5 2 0 2 2 4 5
Cellulose derivatives 5-10 HPMC is the most common
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Antifrictional Agents Antifrictional Agent


Soluble lubricants Insoluble lubricants Glidants Antiadherents

 Sequential addition, PEGs (4000, 6000, 8000) Stearates (Mg, Zn, Ca) Starch Starch
 Final mixing, avoid overmixing Lauryl sulfates (Na, Mg) Talc Talc Talc
 Glidants
Glidants:: <1% (0.25%
(0.25%-- 0.5%) Glyceryl triacetate Waxes Silicon dioxide Most lubricants
 Enhances fluidity by
Polyoxyethylene monostearate Stearic acid Calcium silicate
 Reducing roughness by filling surface irregulairties
Sucrose monolaurate Paraffins Magnesium carbonate
 Reducing attractive forces by physically separating
the host particles Sodium benzoate Hydrogenated vegetable oil Magnesium oxide
 Modifying electric charges
Light mineral oil
 Acting as moisture scavengers
 Serving as ball bearings between host particles Glyceyl behanate

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Surfactant Hydrophilization

 Increases wetting of the powder mass  Process of spreading a solution of


 Enhances drug dissolution hydrophilic polymer onto the drug in a
 0.1%-- 0.5 % SLS or Na Docusate
0.1% high--shear mixer, the resultant mixture
high
dried and screened
 Offsets waterproofing effect of
hydrophobic lubricants  Improves wettability of poorly soluble
drug

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Adsorbent Flavoring Agent

 Added when hygroscopic ingredients are  Palatable enough to be chewed


 Patient compliance
included in the formula
 Enhanced availability
 Problems in the feed  For patients with difficulty in swallowing whole
 stability tablets
 Sweetening agents
 Dextrose, lactose, mannitol, saccharin, sucrose
 Flavoring agents
 Volatile oils: dissolved in alcohol, spray-
spray-dried
 Added just before compression
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Synthetic Colorants Natural Colorants


Color Source Chemical name solubility Light pH Oxidation Tinting
FD&C Color Common Light Heat Oxidation pH 1-
1-4 pH 5-
5-8 pH 9-
9-14 stability stability stability strength
name stability stability stability stability stability stability
Yellow Annatto extract bixin oil poor fair Fair

Red 3 erythrosine poor Good fair ppt fair Good Curcuma turmeric water poor poor

Synthesized -carotene oil poor poor High


Red 40 Allura red AC Good Good fair Good Good poor
Synthesized riboflavin water poor low good fair
Yellow 5 Tartrazine Good Good fair Good Good poor
Red Cochineal Carminic acid water poor poor

Yellow 6 Sunset fair Good fair Good Good poor Beet betacyanins water poor 4-5 poor
yellow
White Synthesized Titanium good good
Blue 1 Brilliant blue fair Good fair poor Good poor dioxide
Orange crocus saffron water poor fair
Blue 2 Indigotine poor fair poor Good Good poor
Purple Grape skin extract anthocyanin water poor low poor poor
Green 3 Fast green fair Good poor poor Good poor
Brown Synthesized Iron oxides good good

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Processing Conditions Powder Mixing

 Powder Mixing  One of the more difficult unit operations


 Granulation (Wet, Dry, Hot Melt)  Perfect homogeneity is practically
unattainable
 Direct Compression  Inherent cohesiveness and resistance to
 Process Parameters movement between individual particles
 Presence of segregative influences in the
 Equipment powder mix
 Optimum mixing time
 Choice of mixer
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Moist Granulation Direct Compression

 For bulky and difficult to compress  Two types:


materials  API is the major component
 Lengthy process  Inherent characteristic of the active ingredient
 API < 10%
 Migration of soluble drug
 Compression aids
 Uneven uniformity  Good mechanical strength with ability to improve
release characteristics
 MCC, spray dried lactose, starch 1500

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General Considerations for


Hard Shell Capsules
 API
 Ideally, dose > 10 mg
 aqueous solubility formulation problem
 Filler
 dosator machine: must ccompressibility
ompressibility
 Antifrictional Agent
 Eases ejection of plugs
 Hydrophilization

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General Considerations for General Considerations for


Liquid--Filled Hard Shell Capsules
Liquid Soft Shell Capsules
 Liquid material must not dissolve, alter or adversely
affect the integrity of the shell  Aim: smallest possible capsule with
 Fill material should be pumpable maximum stability, therapeutic
 Formulation strategies for Liquid-
Liquid-filled Hard Shell effectiveness, and manufacture efficiency
Capsules
 Thixotropic formulations  2.5 >pH> 7.5
 Colloidal silicas
 Thermal setting formulation  More acid pH hydrolyzes gelatin
 PEG 20,000 or 6% of beeswax and/or fumed silicon dioxide
 More alkaline tanning the gelatin
 Mixed thermal/ thixotropic systems
 More lipophilic contents, slower release rate  Fill liquids must flow by gravity at 35
35C

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General Considerations for ISHIKAWA Diagram as a Tool for Risk


Assessment in Formulation Development
Soft Shell Capsules
 Suspension Fill MATERIALS METHODS MEASUREMENT

HPLC
 Micronize all materials Assay Sedimentation Test Calibration

Viscosity Testing

 Suspending agents: Impurity profile

 For oily bases:


Acceptable
 5% beeswax, paraffin wax Suspension
 1-6% animal stearates RH /Temp
Mixing Tank Training
 For non-
non-oily bases:
 1-5% PEG 4000 and PEG 6000 Homogenize
r
 10% solid ninionics ENVIRONMENTAL MAN
MACHINES
 10% solid glycol esters
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Process Parameters

SOURCE: J Pharm Innov (2008) 3:227248

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Process Parameters

FORMULATION OF
LIQUIDS
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Considerations Solubility
Ease of administration for patients who have
difficulty in swallowing solids  Depends on
 Nature and intensity of forces present in the solute
A drug must be in solution in order to be
 Resultant solute-
solute-solvent interaction
absorbed: immediate, rapid, efficient
 Equilibrium solubility
 Solubility
 Determined in a solvent that is similar to the one in
 Preservation the final product
 Subjective Product Characteristics  Fixed temperature
 Stability  Solubility of the solute is not exceeded even at
 Manufacturing temperatures as low as 4oC

Solubility Effect of pH

 pH  pH environment for adequate solubility


 Must not be in conflict with other product
 Co-
Co-Solvency requirements
 Dielectric Constant  Stability, physiologic compatibility
 Adequately buffered
 Solubilization  Adequate capacity in the pH range
 Complexation  Biologically safe
 Little or no deleterious effect on the stability of the final
 Hydrotrophy product
 Permit acceptable flavor and color
 Chemical Modification

Effect of Co-
Co-Solvency

 Co-
Co-solvents increase the water solubility
of the solute
 Ethanol, sorbitol, glycerin, propylene glycol
 Also used to improve the solubility of
volatile constituents used as flavor and
aroma

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Dielectric Constant Solubilization


 A solute shows a preference for solvent  Spontaneous passage of poorly water-
water-soluble
systems having a specific dielectric constant solute molecules into an aqueous solution of a
 Every solute shows a maximum solubility, in soap or a detergent, in which a
any given solvent system at one or more thermodynamically stable solution is formed
specific dielectric constants
 Polyoxyethylene sorbitan, fatty acid esters
 Dielectric constant is the property of a solvent that
relates the amount of energy required to separate (Tween), polyoxyethylene monoalkyl ethers
the same two oppositely charged bodies in the (BRIJ and MYRJ), sucrose monoesters, lanolin
solvent as compared to the energy required to esters and ethers
separate the same two oppositely charged bodies in
a vacuum

Complexation Hydrotrophy
 Addition of complexing agent to promote  increase in solubility in water of various
solubility of the drug
substances owing to the presence of
 Solubility of the drug in a complex is limited by
the solubility of the complex or in some cases, large amounts of additives
the solubility of the complexing agent
 How much drug can be made soluble by a
specific complexing agent
 How complex affects the safety, stability,
efficacy of the final product

Chemical Modification Preservation

 To make a poorly soluble drug to a  Microbial contamination


 Health hazard
water--soluble derivatives
water  Product stability
 New derivatives must be subjected to the  Sources: Raw materials, processing containers and
same testing protocol as the parent equipment, manufacturing environment, operators,
packaging materials, user
compound  Criteria:
 Biological activity  Effective against a broad spectrum of microorganisms
 Acute and chronic toxicity  Physically, chemically and microbiologically stable
 Nontoxic, nonsensitizing, adequately soluble, compatible,
 Pharmaceutical evaluation acceptable taste and odor
 Clinical testing

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Pharmaceutical Subjective Product


Preservatives Characteristics
Acidic Neutral Mercurial Quaternary
Ammonium
Compounds
 Sweetening Agents
Phenol Chlorbutanol Thimerosal Benzalkonium
chloride
Chlorocresol Benzyl alcohol Phenylmercuric Cetylpyridinium
 Viscosity Control
acetate and nitrate chloride
O-phenyl phenol -phenylethyl nitromersol
 Flavors
alcohol
Alkyl esters of
 Appearance
parahydroxybenzoic
acid
Benzoic acids and its
salts
Boric acid and its
salts
Sorbic acid and its
salts

Sweetening Agents Viscosity Control

 Major portion of the formula  Adjunct for palatability


 Sucrose  Improve pourability
 Caplocking  Increase sugar concentration
 Glucose, sorbitol, glycerin  Incorporate viscosity-
viscosity-adding agents
 saccharin  May form molecular complexes and
affect the activity of the parent drug
 May impede drug release and absorption
by resisting dilution by gastrointestinal
fluids

Flavors Flavor Selection


Taste Recommended flavor
sensation
 Effective masking of taste sensations
Salty Butterscotch, maple, apricot, peach, vanilla,
 Flavor adjuncts wintergreen mint
 Desensitizing agents Bitter Wild cherry, walnut, chocolate, mint
 Impart own flavor and odor combinations, passion fruit, mint spice, anise

Sweet Fruit and berry, vanilla

Sour Citrus, licorice, rootbeer, raspberry

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Appearance Chemical Stability

 Color and clarity  Magnified in solutions


 Color should be consistent with flavor  How fast the drug degrades and what are the
consequences of degradation?
 Purification step achieves clarity  Important factors
 Particulate matter  pH
 Lint and fibers from the solvent  Solvents
 Trace quantities of insoluble contaminants  Exposure to light and heat
 Consequences
 Polishing, filtration, clarification
 Suboptimal blood levels
 Extraction of biologically active material from the  Products of degradation may be toxic
filter pad

Physical Stability Manufacturing

 Viscosity, color, clarity, taste, odor  Raw Materials


 Packaging  Equipment
 May decrease bioavailability  Compounding Procedure
 Packaging

Raw Materials Equipment

 Conform to specifications  Mixing tanks equipped with a means of


 Identity, purity, uniformity, microbial agitation, measuring devices for large
contamination and small amounts of solids and liquids,
filtration system for the final polishing
 RMQC and/or sterilization of the solution
 Additional processing  Bulk handling: Tote Bins
 Thoroughly cleaned and sanitized (or
sterilized if possible) before use

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Compounding Procedure Packaging


 Dilute solutions with rapidly dissolving materials
 Charging the solute into the solvent
 Specific method for filling depends on
 Concentrated solutions or solutions with slowly  Liquid characteristics (viscosity, surface
dissolving materials
 Application of heat
tension, foam-
foam-producing qualities,
 Metering purified water into the mixing tank compatibility)
 check malfunctioning metering devices  Type of package
 volumetric (laboratory) vs gravimetric (large scale)
 Solutes present in small concentrations  Production output
 Predissolved prior to mixing with main portion
 complete solution should be confirmed at every stage  Gravimetric, volumetric, constant level
 Amount and type of filter aid methods
 Generally <0.5 g/L

A gem cannot be polished


without friction, nor a man
perfected without trials.

Chinese Proverb

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