Preformulation Studies: Physicochemical Properties and Stability
Preformulation: Physicochemical and Chemical Properties
Preformulation is the study of physical and chemical properties of a drug substance before developing it into a dosage form. It helps to understand drug behavior during formulation.
Goals and Objectives
- To develop a stable, safe, and effective dosage form.
- To determine physicochemical properties of the drug substance.
- To evaluate bioavailability, solubility, and stability parameters.
- To establish drug–excipient compatibility.
- To aid in selecting suitable dosage form and excipients.
Physical Form — Crystalline vs Amorphous
Crystalline: definite lattice, high stability, low solubility, slow dissolution.
Amorphous: irregular molecular arrangement, less stable, higher solubility, rapid dissolution.
Particle Size
Affects dissolution rate, bioavailability, and stability.
- Small particles → faster dissolution but may have poorer stability (more affected by moisture and heat).
- Measured by sieving, microscopy, and laser scattering.
Particle Shape
Particle shape affects flow properties of powders. Spherical particles generally provide better flow than irregular ones.
Flow Properties
Measured by common indices and tests:
- Angle of repose
- Carr’s index
- Hausner ratio
Flow properties determine tableting efficiency and capsule filling efficiency.
Density
Bulk and true density affect powder flow and compaction. Density values are used to calculate flow indices.
Polymorphism
Drugs may exist in multiple crystal forms with different melting points, solubility, and stability. More stable polymorphs tend to be less soluble. Example: chloramphenicol palmitate.
Chemical Degradation Pathways
Common chemical reactions that affect drug stability include:
1. Hydrolysis
Compounds containing ester or amide linkages undergo hydrolysis.
Example: aspirin → salicylic acid + acetic acid.
Prevention: adjust pH, use anhydrous media, add stabilizers.
2. Oxidation
Loss of electrons; occurs in the presence of oxygen and is affected by light, metal ions, and alkalinity.
Prevention: use antioxidants (BHA, BHT), and chelating agents.
3. Reduction
Gain of electrons; occurs less commonly. Example: reduction of ketones.
4. Polymerization
Drug molecules combine to form larger complexes, which affects stability and activity.
5. pKa
pKa determines ionization and therefore influences solubility and absorption.
6. Partition Coefficient (log P)
Log P indicates lipophilicity and helps predict membrane permeability.
7. pH Stability Profile
Drug degradation often depends on pH (acidic or basic hydrolysis).
Drug–Excipient Compatibility Studies
Compatibility studies help ensure that the drug does not chemically or physically react with excipients. Methods used include:
- DSC (differential scanning calorimetry)
- FTIR spectroscopy
- Stress testing (humidity and temperature)
Compatibility studies prevent stability issues in the final dosage form.
Hygroscopic and Deliquescent Properties
Hygroscopic substances absorb moisture from the environment.
Deliquescent substances absorb moisture until they dissolve completely. These properties affect drug stability, packaging, and shelf life.
Hygroscopic substances absorb moisture from the environment.
Deliquescent substances absorb moisture until they dissolve completely. These properties affect drug stability, packaging, and shelf life.
Tablet: Solid Unit Dosage Form
A tablet is a solid unit dosage form prepared by compressing the drug with excipients.
Formulation Considerations
- Diluents – provide bulk (e.g., lactose, microcrystalline cellulose [MCC]).
- Binders – impart cohesiveness (e.g., polyvinylpyrrolidone [PVP], starch paste).
- Disintegrants – promote breakup (e.g., sodium starch glycolate [SSG], cross-linked carboxymethyl cellulose [CCS]).
- Lubricants – reduce friction (e.g., magnesium stearate).
- Glidants – improve flow (e.g., talc).
- Anti-adherents – prevent sticking to punches (e.g., talc, starch).
Tablet Processing Problems
1. Capping
The top portion separates due to air entrapment or poor drying.
2. Lamination
Tablet splits into layers due to over-compression or moisture imbalance.
3. Picking
Material sticks to the punch tip due to insufficient lubrication.
4. Sticking
Material adheres to the punch face because of poor formulation or improper polishing.
5. Mottling
Uneven color distribution caused by dye migration or improper mixing.
Tablet Coating and Types
Film Coating
Thin polymer film (e.g., HPMC, PVP).
Advantages: faster process, less weight gain, elegant appearance.
Sugar Coating
Steps: sealing, subcoating, smoothing, coloring, polishing.
Produces a thick, glossy coating.
Enteric Coating
Protects drug from stomach acid. Uses pH-sensitive polymers (e.g., CAP, HPMCP, Eudragit L/S). Dissolves in the intestine (pH > 5.5).
Coating Defects
Picking, sticking, orange peel, mottling, chipping.
Evaluation
Assess weight gain, appearance, disintegration, and dissolution.
Capsules
Hard Gelatin Capsules
Components: cap and body.
Shell composition: gelatin, water, colorants, preservatives.
Sizes: 000 (largest) to 5 (smallest).
Formulation for filling: powders, pellets, granules, semi-solids.
Manufacturing steps: dipping, spinning, drying, stripping, trimming, joining.
Evaluation: weight variation, moisture content, disintegration.
Soft Gelatin Capsules
Shell composition: gelatin plus plasticizer (glycerin or sorbitol).
Manufacturing: rotary die process.
Applications: oily drugs, vitamins, volatile oils.
Advantages: high bioavailability, easy swallowing, good content uniformity.
Defects: leakage, brittleness.
Sterilization Methods
1. Heat Sterilization
- Moist heat: autoclave at 121°C for 15 minutes.
- Dry heat: 160–180°C for 2 hours.
2. Filtration
Use 0.22 µm membrane filters for heat-sensitive solutions.
3. Radiation
Gamma radiation for suitable products.
4. Gas Sterilization
Ethylene oxide for thermolabile items.
Each method is selected based on drug sensitivity and product type.
Formulation and Preparation of Ointments and Creams
Formulation components:
- Drug
- Base (hydrocarbon, absorption, or water-soluble)
- Preservatives
- Humectants
Preparation Methods
Fusion method: melt the base and incorporate the drug.
Incorporation method: levigate the drug into the base.
Types
- Ointments – greasy
- Creams – oil-in-water (o/w) or water-in-oil (w/o)
- Gels – contain gelling agents
- Pastes – high solid content
Evaluation
Viscosity, spreadability, and drug release characteristics are evaluated.
Suppositories
Bases:
- Cocoa butter
- PEG (polyethylene glycol)
- Glycerinated gelatin
Displacement value: used to calculate the amount of base displaced by the drug.
Evaluation
- Softening point
- Weight variation
- Drug content