PREFORMULATION STUDIES - industrial pharmacy 1 - part 1

 

1. INTRODUCTION

Before developing a formulation like tablets, capsules, liquid orals we study the

suitability of new drug or drug and excipients for the chosen formulation which is called

preformulation.

1.1 Definition

Preformulation may be defined as a stage of the research and development process

where the preformulation scientist characterizes the physical, chemical, biopharmaceutical

and mechanical properties of a new drug substance, in order to develop stable, safe and

effective dosage form.

1.2 Objectives

To generate useful information to the formulator to design an optimum drug delivery

system. The preformulation investigations confirm that there are no significant barriers to

the compound’s development as a marketed drug. The formulation scientist uses this

information to develop dosage forms.

 

1.3 Goals of Preformulation

• To find the necessary physicochemical properties like solubility, crystal form of newdrug substances.
• To determine kinetic release of drug from dosage form.
• To establish physical characteristics.
• To establish compatibility (no interaction) with common excipients.

1.4 Preformulation Factors

It is study about physical and chemical properties of drug substance prior formulation is

called as preformulation.

They are:

• pH /pka
• Solubility
• Thermal/heat effect
• Dissociation constant
• Compatabilty studies - FTIR / DSC
• Oxidation and reduction
• Particle size

2. PHYSICAL PROPERTIES

It is vital to understand the physical description of a drug substance prior to dosage form development. Most drugs in use nowadays are solid materials and less number are liquid in nature. 

Flowability of powder and chemical stability depends on the habit and internal structure of a drug.

Principal Areas of Preformulation :

(I) Nature of Solid Drug:

1. Crystallinity and polymorphism
2. Hygroscopicity
3. Fine particle characterization
4. Powder flow

(II) Solubility Data:

1. Ionization constant – pKa v (- log Ka)
2. pH solubility profile
3. Common ion effect – KSP.
4. Thermal effects
5. Solubilization
6. Partition coefficient
7. Dissolution

(III) Stability Analysis:

1. Stability in toxicology formulation
2. Solution stability
3. Solid state stability

2.1 Nature of Solid Drug

2.1.1 Crystallinity and Polymorphism

Polymorphs: 

When a substance is in more than one crystalline form, the various forms are called polymorphs and the phenomenon as polymorphism.

e.g. Chloramphenicol palmitate has three polymorphs: A, B and C. Spironolactone exhibits 6 polymorphs.

Various polymorphs can be prepared by crystallizing the drug from different drugs under various conditions. Depending on their relative stability, one of the different polymorphic forms will be physically more stable than the others. Such a stable polymorph represents the lowest thermodynamic energy state, has highest melting point and least solubility. The representing polymorphs are called metastable forms which represent higher thermodynamic energy state; the metastable forms have a thermodynamic tendency to convert to the stable form. A metastable form cannot be called unstable because if it is kept dry, it will remain stable for years.

Analytical Methods for Characterization of Solid Forms:

Methods of studying solid forms are listed as below (amount of drug required for study):

• Microscopy (1 mg)
• Hot stage microscopy (1 mg)
• Differential Scanning Calorimetry (DSC) (2 - 5 mg)
• Differential Thermal Analysis (DTA) (2 - 5 mg)
• Thermogravimetric Analysis (10 mg)
• Infrared Spectroscopy (2 - 20 mg)
• X-ray Powder Diffraction (500 mg)
• Scanning Electron Microscopy (2 mg)
• Dissolution / Solubility Analysis (mg - g)

2.1.2 Hygroscopicity

Definition: 

Many pharmaceutical materials have a tendency to adsorb atmospheric moisture (especially water-soluble salt forms). They are called hygroscopic materials and this phenomenon is known as hygroscopicity.

Equilibrium moisture content depends upon:

(i) The atmospheric humidity

(ii) Temperature

Deliquescent materials:

(i) Surface area

(ii) Exposure time

(iii) Mechanism of moisture uptake.

They absorb sufficient amount of moisture and dissolve completely in it. (e.g. anhydrous calcium chloride.

Tests of Hygroscopicity

Procedure: Bulk drug samples are placed in open containers with thin powder bed to

assure maximum atmospheric exposure. These samples are then exposed to a range of

controlled relative humidity (Relative Humidity) environments prepared with saturated

aqueous salt solutions.

The amount of moisture adsorbed can be determined by the following methods:

(i) Gravimetry

(ii) Thermogravimetric analysis (TGA)

(iii) Karl-Fischer titration (KF-titration)

(iv) Gas chromatography (GC)

Time of monitoring depends on the purpose:

(i) For the purpose of ‘handling’ data points from 0 to 24 hours are taken

(ii) For the purpose of ‘storage’ data points from 0 to 12 weeks are taken.

Significance of Hygroscopicity Test:

 To decide

1. The storage condition i.e. at low humidity environment.
2. Special packaging – e.g. with desiccant.

Moisture level in a powder sample may affect the flowability and compatibility which,

are important factors during tableting and capsule filling.

2.1.3 Characterization of Fine Particle

Parameters those are measured:

1. Particle size and size-distribution
2. Shape of the particle
3. Surface morphology of the particles
4. Zeta potential

Instrumental Methods of Particle Size Characterization:

(i) Light Microscope:

• First a standard graticule (BS 3625) is standardized with a stage micrometer. Then small number of particles are spread over a glass slide and placed on the stage of the microscope. Particles are focussed and the particle diameters are measured. Several hundred particles are measured and reported as a histogram.

• Disadvantage: The procedure is tedious (means it takes slow and monotonous long time.)

(ii) Stream counting devices:

Examples:

• Coulter counter – electrical sensing zone method
• HIAC – counter – optical sensing zone
• Malvern particle and droplet sizer – Laser diffraction method.

Procedure: Vacuum Amplifier and Counter Stirrer Electrodes Orifice:

• Samples prepared for analysis are dispersed in a conducting medium (e.g. saline) with the help of ultrasound and a few drops of surfactant (to disperse the particles uniformly). A known volume (0.5 to 2 mL) of this suspension is then drawn into a tube through a small aperture (0.4 to 800 μm diameter) across which a voltage is applied.

• As each particle passes through the hole, it is counted and sized according to the resistance generated by displacing that particle’s volume of conducting medium.

• Size distribution is reported as histogram.

(iii) Sieve analysis:

• A powder sample is passed through a standard sieve set. The particle size is plotted against % weight retained on each sieve.

• Use: This method is used generally for large samples.

Source of Variation of Bulk Density:

Method of crystallization, milling, formulation

Methods of correction:

By milling, slugging or formulation

Significance:

• Bulk density is required during the selection of capsule size for a high dose drug.
• In case of low dose drug mixing with excipients is a problem if the bulk densities of the drug and excipients have large difference.
• Near the bottom, a set of scanning coils moves the focussed beam back and forth across the specimen, row by row.
• As the electron beam hits each spot on the sample, secondary electrons are knocked loose from its surface. A detector counts these electrons and sends the signals to an amplifier.
• The final image is built up from the number of electrons emitted from each spot on the sample.

2.1.4 Powder flow properties:

Powder flow properties depend on

1. particle size
2. density
3. shape
4.  electrostatic charge and adsorbed moisture

that may arise from processing or formulation.

A free-flowing powder may become cohesive during development. This problem may be

solved by any of the following ways:

1. by granulation
2. by densification via slugging
3. by filling special auger feed equipment (in case of powder)
4. by changing the formulation.

2.2 Solubility Data

2.2.1 Ionization constant – pKa v (- log Ka)

pKa Determination:

• When a weakly acidic or basic drug partially ionizes in GI fluid, generally, the unionized molecules are absorbed quickly.
• Handerson-Hasselbach equation provides an estimate of the ionized and unionized drug concentration at a particular pH.

Methods of Determination of pKa of a Drug:

1. Detection of spectral change by UV or visible spectroscopy at a range of pH:

               Advantage: Dilute aqueous solutions can be analyzed by this method.

     2. Potentiometric titration:

             Advantage: Maximum sensitivity for compounds with pKa in the range of 3 to 10.

2.2.2 pH solubility profile

 

 pKa Determination: 

The Henderson – Hasseslebach equation provides an estimate of the ionized and unionized drug concentration at a particular pH.

For acidic drugs,

pH = pKa + log (ionized drug / un-ionized drug)

For basic drugs,

pH = pKa + log (unionized drug / ionized drug)

• Buffers, temperature, ionic strength and cosolvent can affect the pKa value.
• Potentiometric titration offers maximum sensitivity for compounds with pKa values in the range of 3-10.

2.2.4 Thermal effects

Drugs which are unstable to heat requires refrigerative storage or lyophilisation (these products must be used within short periods)

 If it is endothermic > ΔH is + ve 

Increase in temperature > Increase in drug solubility

If it is exothermic > ΔH is – ve 

Increase in temperature > Decrease in drug solubility

For determining ΔH 
ln S = − ΔH /RT + C

S = molar solubility at temperature, T = temperature in Kelvin, R = gas constant

2.2.5 Solubilization

• Solubilization is increased by cosolvent addition.

• E.g. Propylene glycol solubilizes drug molecules by disrupting the hydrophobic

interactions of water.

More non-polar the solute so, Greater is the solubilisation achieved by cosolvent addition

2.2.6 Partition coefficient

Partition coefficient is defined, as the ratio of un-ionized drug concentrations between the organic and aqueous phases, at equilibrium.

Generally, 2-octanol and chloroform are taken as the oil phase. m equilibrium

Significance: Drug molecules having higher KO/W will cross the lipid cell membrane.

2.2.7 Dissolution

chemical properties - preformulation (click here)