Pharmaceutical Pre-formulation

Overview

• Preformulation: early stage of drug development focused on evaluating the physicochemical properties of potential drug candidates. This information is crucial for designing the final dosage form.

• Characterization is essential for assessing:

  • Efficacy

  • Physicochemical stability

  • Bioavailability

  • Excipient interactions

Drug Selection in Discovery Phase

• Multiple candidates may target the same biological site.

• Efficacy alone is insufficient; consider:

  • Solubility

  • Stability

  • Bioavailability

  • Drug-excipient interactions

Key Preformulation Parameters

1. Solubility

• FIRST parameter assessed

• Target values:

  • IV/oral liquids: > 1 mg/mL

  • Oral solids: > 10 mg/mL

  • Poor solubility: < 1 mg/mL → salts, cocrystals, solid dispersions, micronization

Assay Method

• UV Spectroscopy (primary)

  • Requires chromophore

  • Beer-Lambert's Law

• HPLC: Quantitative and qualitative analysis

2. Assay Development

• Initial step: Small drug amount used

• Uses saturated solutions to determine:

  • Solubility

  • log P (after adding octanol)

• Early formulation (IV/oral liquids) informs:

  • Dose

  • Bioavailability

  • Toxicity

3. Melting Point & Enthalpy of Fusion

• Measured via DSC (Differential Scanning Calorimetry)

  • ENDOTHERMIC PEAK = MELTING

  • AUC = Enthalpy of fusion

    • Low AUC → high solubility

• Solid form affects properties:

  • Polymorphs

  • Amorphous (no MP, variable ΔHf)

4. pKa and Ionization

• 60% of drugs ionize between pH 2–12

• Affects solubility in different GI pH environments

Henderson-Hasselbalch Equation

• Predicts ionization from pKa and pH

• IONISED form → MORE SOLUBLE

• UNIONISED form → MORE PERMEABLE

Measurement

• Potentiometric titration (primary)

• Also: Conductivity, Spectroscopy

5. Dissolution Rate

• Not the same as solubility (rate ≠ extent)

• Noyes-Whitney equation governs dissolution

Intrinsic Dissolution Rate (IDR)

• Ideal: > 1 mg/cm²/min

• Controlled test where SURFACE AREA IS CONSTANT

• Measured by rotating compact disc in dissolution medium

6. Partition Coefficient (Log P)

• Measures lipophilicity (unionized drugs only)

• Reflects drug’s ability to cross lipid membranes

Methods

• Shake Flask

• TLC

• HPLC

7. Salt Formation

• Enhances solubility and dissolution

• Formed when:

  • Weak acid + Strong base

  • Weak base + Strong acid

  • Drug pKa > 5

Salt Selection Criteria

• ΔpKa > 3 for stable salt

  • 0–3: uncertain

  • < 0: cocrystals

Salt Formers

• 1st Class: Physiological ions (e.g. Na⁺, HCl)

• 2nd Class: Non-natural but common (e.g. mesylates)

• 3rd Class: Rare, used in special cases

8. Salt Screening

• Microwell plate: 0.5 mg drug + counter-ion

• Crystal analysis:

  • XRPD → polymorphs

  • DSC, HSM → melting, thermal properties

  • TGA, DVS → hydration/hygroscopicity

9. Hygroscopicity

• Tendency to absorb water

• Impacts flowability, chemical stability

• Salts more hygroscopic than free base/acid

• Measurement:

  • DVS

  • TGA

  • Karl Fischer titration

10. Polymorphism

• Different crystal forms of same drug

• Affects:

  • Melting point

  • Solubility

  • Bioavailability

  • Processability (e.g. Paracetamol I vs II)

• Detection: XRPD, DSC

11. Bulk Powder Properties

• Particle size/shape: Light microscope, SEM

• Flow properties:

  • Angle of repose

  • Carr’s index

  • Hausner’s ratio

• Compaction:

  • Most drugs have poor compressibility → need excipients

Summary Table: Molecular Properties & Techniques