R & D (M.Pharm Pharmaceutics)

What is Preformulation ?
It can be defined as an investigation of physical and chemical properties of a drug substance - alone and when combined with excipients.  Preformulation is the first step in the rational development of dosage forms of a drug substance.

The overall objective of preformulation testing is to generate information useful to the formulator in developing stable and bioavailable dosage forms which can be mass-produced.

Properties associated with drug
Bulk properties (Physical Properties)  Physicochemical properties  Stability considerations  Biopharmaceutical considerations

Bulk / Physical Properties

Bulk / Physical Properties
Organoleptic  Particle size, shape, and surface area  Crystallinity and polymorphism  Water adsorption / Hygroscopicity.
 

Bulk / Physical Properties
Bulk density  Adhesion  Powder flow  Compressibility

Organoleptic Properties

Colourcan be useful when describing different batches of drug it can sometimes be used as an indicator of solvent presence or, more importantly, of degradation. In addition, subtle differences in colour may be due to variations in the particle size distribution.  Usually colour is subjective and is based on individual perception; however, more quantitative measurements can be obtained by using, e.g.,tristimulus colorimetry  The shelf life of the formulations could be specified using the Commission Internationale de’Ecalarage (CIE) system for colour.

No strong odours should be present.  Any deviation from the substance’s characteristic odour is to be considered and checked for degradations in the substance.


Unpalatable  decreasing the solubility (in case of DPI’s)   supressedby  coating  flavours


Particle size, shape, and surface area

Particle size:
 General

Techniques For Determining Particle Size
 Microscopy  Sieving

(Quantitative particle size distribution analysis)  Electronic means
  

Blockage of electrical conductivity path (coulter counter) Light scattering Laser scattering

Common Techniques for Measuring Fine Particles of Various Sizes

 


Particle size (µ m) 1 - 100 > 50 >1 1 - 50 < 50 >1 0.5 - 50

Microscopic Sieve Sedimentation Elutriation Centrifugal Permeability Light scattering

Determination of Surface Area
Brunauer-Emmett-Teller (BET) method  Dynamic method of gas adsorption

Some facts of surface area

At relatively large diameters, the specific surface area is insensitive to an increase in diameter At very small diameters the surface area is comparatively very sensitive. Relatively high surface area most often reflects a relatively small particle size, except porous or strongly agglomerated mass Small particles (thus of high surface area) agglomerate more readily, and often to render the inner pores and

Particle shape
 

Particle shape is of consideration in the flow properties of the drug. The particle shape (crystalline structure) can be changed to our convenience and requirements by controlled recrystallization.

Crystallinity and polymorphism

Polymorphism is a solid crystalline phase of a given compound resulting from the possibility of at least two different arrangements of that compound in the solid state.

Polymorphism study is conducted to:

Manufacture the desired forms consistently Understand the effects of pharmaceutical manipulations , e.g : granulation, milling and compression Evaluate and predict the storage conditions on dosage forms e.g : crystal growth in creams, suspensions and MDI’s.

Polymorphism can be screened by:
      

Crystallization from different solvents at different speeds and temperatures Precipitation Concentration or evaporation Crystallization from the melt Grinding and compression Lyophilization Spray drying

Crystal habit

Crystal morphology or habit is important, since it can influence many properties of the compound. For example, powder flow properties, compaction and stability have all been found to be dependent on crystal morphology.

Examples of crystal habits

Overcoming crystallinity problems

If a particular formulation is unstable or having problem in formulation due to the crystal habit of the substance, then it is recrystallized from different solvents to obtain the required crystal habit. The effect of impurities on the crystal habit should not be overlooked, as these can act as crystal poisons or promote growth in a particular crystallographic direction

The most accurate way of determining the symmetry of a crystal is to use an optical goniometer to measure the angles between the crystal faces.


Many compounds and salts are sensitive to the presence of water vapour or moisture. When compounds interact with moisture, they retain the water by either bulk or surface adsorption, capillary condensation, chemical reaction. Deliquescence is where a solid dissolves and saturates a thin film of water on its

Degree of hygroscopicity

Slightly hygroscopic: Increase in mass is less than 2 percent m/m and equal to or greater than 0.2 percent m/m. Hygroscopic: Increase in mass is less than 15 percent m/m and equal to or greater than 0.2 percent m/m.

Very hygroscopic: Increase in mass is equal to or greater than 15 percent m/m. Deliquescent: Sufficient water is absorbed to form a liquid.

Bulk density

The density of a powder sample is usually referred to as the bulk density, and the volume includes both the particulate volume and the pore volume. Minimum bulk density is when the volume of the powder is at a maximum, caused by aeration, just prior to complete breakup of the bulk.

Poured bulk density is when the volume is measured after pouring powder into a cylinder, creating a relatively loose structure. Tapped bulk density is, in theory, the maximum bulk density that can be achieved without deformation of the particles.

Powder flow

Good flow properties are a prerequisite for the successful manufacture of both tablets and powder-filled hard gelatin capsules. It is a property of all powders to resist the differential movement between particles when subjected to external stresses. This resistance is due to the cohesive forces between particles.

Three principal types of interparticle force have been identified
  

forces due to electrostatic charging vander Waals forces forces due to moisture

Measuring Powder Flow Properties

Shear Cell Method

Powders with particles below 50 µm will generally exhibit irregular or no flow due to vander Waals forces Particle shape is also important; for example, the force between a sphere and plane surface is about twice that between two equal sized spheres.

Changes in Bulk Density:

The increase in bulk density of a powder is related to the cohesivity of a powder. Ratios of the poured to tapped bulk densities are expressed in two ways to give indices of flowability.

The Hausner Ratio varies from about 1.2 for a free-flowing powder to 1.6 for cohesive powders.

The Carr Index classifications are

Angle of Repose

If powder is poured from a funnel onto a horizontal surface, it will form a cone. The angle between the sides of the cone and the horizontal is referred to as the angle of repose. angles less than 30°are usually indicative of good flow, while powders with angles greater than 40°are likely to be problematic.

Physico-chemical properties

Physico-chemical properties
   

Solubility analysis Ionization Partition coefficients Dissolution


Solubility is the extent of drug that goes into solution form.

Solubility standards

Many drugs are ionizable organic compounds, and thus there are a number of parameters that will determine the solubility of a compound. These parameters include, e.g., molecular size and substituent groups on the molecule, degree of ionization, ionic strength, salt form, temperature, crystal properties and complexation.

Determination of Solubility
Semiquantitative determination:
Solvent (fixed volume) Vigorously shaking Examine visually

Adding solute in small incremental amounts

Undissolved solute particles ?



Estimated solubility

Total amount added up

Accurately Quantitative determination:
Excess drug powder 150 mg/ml (15 %) + solvent Ampul/vial (2-5 ml) Shaking at constant temperature (25 or 37 oC) 2 - 8 oC ? 48 hr

The first few ml’s of the filtrates should be discarded due to possible filter adsorption

Determine the drug concentration in the filtrate
Same concentration ?

Membrane filter 0.45 µ m 72 hr Membrane filter 0.45 µ m ? hr Membrane filter 0.45 µ m

Determine the drug concentration in the filtrate Determine the drug concentration in the filtrate


Highly insoluble drug administered in small doses may exhibit good absorption Unstable drug in highly acidic environment of stomach, high solubility and consequent rapid dissolution could result in a decreased bioavailability The solubility of every new drug must be determined as a function of pH over the physiological pH

Problems in Solubility Determination of Poorly Soluble Compounds

Solubilities could be overestimated due to the presence of soluble impurities  Saturation solubility is not reached in a reasonable length of time unless the amount of solid used is greatly in excess of that needed to saturation

Many compounds in solution degrade, thus making an accurate determination of solubility difficult  Difficulty is also encountered in the determination of solubility of metastable forms that transform to more stable forms

pH-Solubility Profile
Excess drug powder Stir in beaker with distilled water Continuous stirring of suspension


Measure pH of suspension


Add acid/base



5 Indomethacin (weak acid)

Log aqueous solubility (µ mol)



Chlorpromazine (weak base)



Oxytetracycline (amphoteric) 2 4 6 8 10 12 14


Enhancing solubility
  

Salt forms Complexation Using mixed solvents

Use more soluble metastable polymorph  Use of complexation (eg. Ribloflavin-xanthines complex)  Use of suitable surfactant

Salt forms

Drugs which are acidic or basic in nature, if needed are converted to a stable salt form.

alclofenac, diclofenac, fenbufen, ibuprofen, naproxen  Weak acid pKa ~ 4, low solubility  Salt forms: sodium, N-(2-hydroxy ethyl) piperazinium arginium  N-methylglucosammonium



diclofenac (free acid) : 0.8 x 10 M (25 oC) diclofenac sodium : 24.5 mg/ml

 


enoxacin, norfloxacin, ciprofloxacin
lactate, acetate, gluconate, galacturonate, aspartate, glutamate, etc. < 0.1 mg/ml (25 oC) > 100 mg/ml (25 oC)

 

Salt forms

Solubility  Free base :  Salt forms :


Dissolution is the dynamic process by which a material is dissolved in a solvent and is characterised by a rate (amount dissolved per time unit)

kd << ka  “dissolution rate-limited” kd


Absorption site (gi-tract)


C, Vc Xc


Central compartment (blood circulation)

Diagram showing dissolution and absorption of solid dosage form into blood circulation

Determination of dissolution

Dissolution can be determined by
 Rotating 

disk method (Woods apparatus)  Nelson constant surface method

Rotating-disk method (Wood apparatus)
Stirring shaft

Lower punch Rubber gasket Tablet die

Compressed tablet Dissolution medium

Nelson Constant Surface method
Dissolution medium Rotating Paddle Tablet surface

Hardened wax or paraffin

Particulate Dissolution
Particulate dissolution is used to study the influence on dissolution of particle size, surface area, and mixing with excipients.  The rate of dissolution normally increased with a decrease in the particle size.

Occasionally, however, an inverse relationship of particle size to dissolution is encountered. This may be explained on the basis of effective or available, rather than absolute, surface area; and it is caused by incomplete wetting of the powder. Incorporation of a surfactant in the dissolution medium may provide the expected relationship.

Means of enhancing the slow dissolution:
In absence of more soluble physical or chemical form of the drug  Particle size reduction (most commonly used).  Enhanced surface area by adsorbing the drug on an inert excipient with a high surface area, i.e., fumed silicon dioxide.  Comelting, coprecipitating, or triturating the drug with some excipients.  Incorporation of suitable surfactant.

Partition Coefficient
 

Like biological membrane in general, the gi membranes are largely lipoidal in character. The rate and extent of absorption decreased with the increasing polarity of molecules. Partition coefficient (distribution coefficient): the ratio in which a solute distributes itself between the two phases of two immiscible liquids that are in contact with each other (mostly n-octanol/water).

Partition coefficient K O/W can be determined by spectrophoteometric methods.

Ionization constant
 

  

The unionized species are more lipid-soluble and hence more readily absorbed. The gi absorption of weakly acidic or basic drugs is related to the fraction of unionized drug in solution. Factors affecting absorption: - pH at the site of absorption - Ionization constant - Lipid solubility of unionized species

Henderson-Hasselbalch equation For acids:
 

pH = pKa + log [ionized form]/ [unionized form] pH = pKa + log [unionized form]/ [ionized form]

 

For bases:

Determination of Ionization Constant Potentiometric pH-Titration  pH-Spectrophotometry Method  pH-Solubility Analysis

pKa Determinations

Many potential candidate drugs are weak acids or bases, therefore, one of the most important determinations carried out prior to development is the pKa or ionization constant. Strong acids, e.g., HCl, are ionized at all pH values, whereas the ionization of weak acids is dependent on pH. It is useful to know the extent to which the molecule is ionized at a certain pH, since properties such as solubility, stability, drug absorption and activity are affected

Methods for the determination of pKa
      

Potentiometric titration UV spectotroscopy Solubility measurements HPLC techniques Capillary zone electrophoresis Foaming activity

Stability considerations


Solid state
Relative Humidity  Compatibility

 pH  Buffer  Solvent  Temperature 

Compatibility with excipients
 All

the drug substances are checked for their compatibility with the excipients, and their stability in the dosage form.

Biopharmaceutical considerations

 Route  Rate  Extent  Mechanism  Absorption

windows  Food effects

 First

pass metabolism  Enzyme induction  Metabolism in GIT

Duration of action
 Dosing  Controlled


 

 

Modern Pharmaceutics – Gilbert.S.Banker Theory and Practice of Industrial Pharmacy – Leon Lachman Solid Dosage Forms Vol1 - Lachman & Lieberman Liquid Dosage Forms (Parenterals)Vol 1 - Lachman & Lieberman Preformulation in Solid Dosage Form Development - Moji Christianah Adeyeye, Harry G. Brittain. Stability of Drugs and Dosage Forms - Sumie Yoshioka Pharmaceutical Preformulation And Formulation A Practical Guide From Candidate Drug Selection


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