Unit 1: Preformulation Studies

2.1 Preformulation Studies

Definition

Preformulation is the systematic evaluation of a drug’s physical and chemical properties to guide the development of a stable, effective, and manufacturable dosage form. It bridges the gap between an active pharmaceutical ingredient (API) and the final product by identifying formulation challenges early.

2.1.1 Physical Properties

• Solubility

  • Definition: The ability of the API to dissolve in various solvents (water, buffers, lipids).

  • Importance: Determines bioavailability, selection of solvent systems, and need for solubility‐enhancing techniques (e.g., salt formation, cyclodextrin complexation).

• Partition Coefficient (Log P/Log D)

  • Definition: Ratio of drug concentration in octanol versus water phases at equilibrium (Log P for unionized; Log D accounts for ionization at a given pH).

  • Importance: Predicts membrane permeability, distribution, and potential for tissue accumulation.

• Particle Size & Surface Area

  • Definition: Measurement of API particle dimensions and total surface area.

  • Importance: Influences dissolution rate, content uniformity, flow properties, and bioavailability; may require milling or micronization.

2.1.2 Chemical Properties

• pKa and Ionization

  • Definition: pH at which 50% of drug is ionized.

  • Importance: Affects solubility, membrane permeability, and selection of pH in formulations to maximize stability and absorption.

• Stability Profile

  • Definition: Assessment of API chemical degradation under stress conditions (heat, humidity, light, oxidation, pH extremes).

  • Importance: Guides selection of excipients, packaging, and storage conditions; shelf‑life estimation.

• Polymorphism

  • Definition: Existence of multiple crystalline forms of the same API.

  • Importance: Different polymorphs can vary in solubility, stability, and compressibility; selection of the optimal form is critical.

2.1.3 Biopharmaceutics Classification System (BCS)

• BCS Classes

  1. Class I: High solubility, high permeability

  2. Class II: Low solubility, high permeability

  3. Class III: High solubility, low permeability

  4. Class IV: Low solubility, low permeability

• Application:

  • Determines formulation strategy (e.g., solubility enhancement for Class II; permeability enhancers or particle size reduction for Class III).

  • Regulatory impact on bioequivalence waivers.

2.1.4 Stability Considerations

• Forced‑Degradation Studies

  • Purpose: Identify degradation pathways and major impurities by exposing API to stress (acid/base hydrolysis, oxidation, photolysis, thermal).

• Compatibility with Excipients

  • Purpose: Evaluate interactions between API and common excipients (lactose, MCC, binders) via differential scanning calorimetry (DSC), FTIR.

• Design of Experiments (DoE)

  • Purpose: Systematically optimize formulation parameters (pH, excipient ratios, processing conditions) to maximize stability and performance.

Key Takeaways for Exams

1. Define preformulation and explain its role in dosage‐form development.

2. Correlate solubility, partition coefficient, and particle size with bioavailability and manufacturing processes.

3. Classify APIs by BCS and propose appropriate formulation strategies.

4. Design stability studies to identify degradation mechanisms and select compatible excipients.

5. Apply DoE principles to optimize preformulation variables for robust product performance

Unit 2: Tablets

2.2 Tablets

Definition

Tablets are solid dosage forms containing APIs and excipients, prepared by compressing a powder or granulate into a defined shape and size. They are the most common oral formulation due to ease of administration, manufacturing scalability, and dose accuracy.

2.2.1 Formulation Components

• Active Pharmaceutical Ingredient (API)

  • Provides the therapeutic effect; must be compatible with excipients and stable under compression.

• Diluents (Fillers)

  • e.g., Lactose, Microcrystalline Cellulose: add bulk to low‑dose APIs and improve flow.

• Binders (Granulating Agents)

  • e.g., Povidone (PVP), Hydroxypropyl Methylcellulose (HPMC): promote cohesion of powder particles.

• Disintegrants

  • e.g., Crospovidone, Sodium Starch Glycolate: swell or wick water into tablet to facilitate breakup upon ingestion.

• Lubricants & Glidants

  • e.g., Magnesium Stearate (lubricant), Colloidal Silicon Dioxide (glidant): reduce friction during tablet ejection and improve powder flow.

• Coating Polymers & Additives

  • e.g., Film‑forming polymers (HPMC, Eudragit), plasticizers (triethyl citrate), colorants: protect tablet, mask taste, control release, or enhance appearance.

2.2.2 Granulation Techniques

• Wet Granulation

  • Process: Mix powders → add binder solution → form wet mass → pass through sieve → dry granules → size‑screen.

  • Advantages: Improves flow, uniformity, compressibility; suitable for poorly flowing APIs.

  • Considerations: Drying time/temperature to avoid API degradation.

• Dry Granulation (Slugging/Roller Compaction)

  • Process: Compress powder into slugs or sheets, mill to granules.

  • Advantages: No water or heat—ideal for moisture/heat‑sensitive APIs.

  • Limitations: Higher equipment cost; possible segregation.

• Direct Compression

  • Process: Blend API with directly compressible excipients; compress into tablets.

  • Advantages: Simplest; avoids granulation steps.

  • Limitations: Requires excipients with excellent flow and binding; not suitable for low‑dose or poor‑flow APIs.

2.2.3 Compression

• Tablet Press Types

  • Single‑Punch Press: For small batches and R&D.

  • Rotary Press: High‑throughput industrial production.

• Compression Parameters

  • Pre‑compression Force: Consolidates powder before final compaction.

  • Main Compression Force: Determines tablet hardness, porosity, and dissolution rate.

  • Dwell Time: Affects bonding; longer dwell increases hardness.

• Common Defects & Remedies

  • Capping/Lamination: Incomplete bonding—adjust compression force or granule moisture.

  • Mottling: Uneven color distribution—improve pigment dispersion or coating process.

2.2.4 Coating

• Objectives

  • Protect API from moisture/light.

  • Mask unpleasant taste or odor.

  • Modify drug release (enteric, sustained‑release).

  • Improve aesthetics and swallowability.

• Techniques

  • Sugar Coating: Multiple layers of syrup and powder—time‑consuming, bulky.

  • Film Coating: Thin polymeric film sprayed on tablets—faster, lightweight, versatile for controlled release.

  • Enteric Coating: pH‑sensitive polymers (Eudragit® L/S) to prevent drug release in stomach.

• Process Parameters

  • Spray rate, inlet/outlet temperature, pan speed, and drying time must be optimized to avoid defects (bridging, peeling).

2.2.5 Quality Control Tests

• Physical Tests

  • Weight Variation: Ensures uniformity of dosage units.

  • Hardness (Crushing Strength): Measured by tablet hardness tester—impacts friability and disintegration.

  • Friability: Roche friabilator assesses resistance to abrasion; acceptable loss typically < 1%.

• Chemical Tests

  • Assay & Content Uniformity: HPLC or spectrophotometry to quantify API per tablet; must meet pharmacopeial limits (85–115% of label claim).

  • Dissolution Testing: USP apparatus measures drug release profile in specified medium; critical for bioavailability.

• Disintegration Test

  • Procedure: USP disintegration apparatus; tablets must break down within specified time in simulated GI fluid.

Key Takeaways for Exams

1. List all excipient categories in a tablet formulation and explain their functions.

2. Compare wet versus dry granulation, including advantages and when each is preferred.

3. Describe the compression process parameters and how they affect tablet quality.

4. Differentiate sugar coating from film coating and identify when enteric coating is required.

5. Outline essential QC tests for tablets and the acceptance criteria for each.

Unit 3: Capsules & Pellets

2.3 Capsules & Pellets

Definition

Capsules are solid dosage forms in which the API and excipients are enclosed within a hard or soft shell, typically made of gelatin or alternative polymers. Pellets are small, free‑flowing, spherical granules manufactured to deliver drugs with modified release profiles.

2.3.1 Hard Gelatin Capsules

• Composition & Structure

  • Two-piece shells: a longer “body” and shorter “cap” that fit together.

  • Made from gelatin (animal‑derived or vegetarian substitutes), plasticizers (glycerin, sorbitol), colorants.

• Advantages

  • Simple to fill with powders, granules, or pellets.

  • Tasteless shell masks unpleasant API flavor.

  • Flexible dosing by varying fill weight or combining capsules.

• Manufacturing Process

  1. Dipping & Drying: Stainless‑steel pins dipped into gelatin solution, dried to form uniform shells.

  2. Stripping & Trimming: Capsules stripped from pins, trimmed to standard length.

  3. Filling: Shells filled using manual (Roto‑caps) or automatic (dosator, tamp‑blast) fillers.

  4. Joining & Sealing: Cap and body joined; optional banding or locking to prevent tampering.

• Quality Control Tests

  • Weight Variation: Ensures uniform fill weight.

  • Disintegration: Shell must rupture within specified time in aqueous medium.

  • Dissolution: For modified‑release fills, release profile must meet pharmacopeial criteria.

  • Moisture Content: TGA or Karl Fischer titration to ensure shell integrity (typically 13–16%).

2.3.2 Soft Gelatin Capsules

• Composition & Structure

  • One‑piece, hermetically sealed shells containing liquid, paste, or semi‑solid fills.

  • Gelatin blended with plasticizer to impart elasticity; may include water, preservatives, opacifiers.

• Advantages

  • Ideal for oils, suspensions, self‑emulsifying drug delivery systems (SEDDS).

  • Improved bioavailability for lipophilic APIs.

  • Tamper‑evident—hermetic seal prevents leakage.

• Manufacturing Process

  1. Gelatin Melting & Homogenization: Gelatin/plasticizer/water mixture heated and homogenized.

  2. Encapsulation: Rotary die process meters shell material and fill simultaneously; dies form, fill, and seal capsules.

  3. Drying & Polishing: Capsules dried on trays or tumblers; polished to remove surface moisture.

• Quality Control Tests

  • Leakage/Integrity: Visual inspection, dye‑penetration tests.

  • Uniformity of Fill Weight & Content: Weigh individual capsules and assay API.

  • Disintegration/Dissolution: Validate fill release characteristics.

  • Moisture & Plasticizer Content: Ensures proper shell flexibility without brittleness.

2.3.3 Pelletization Techniques

• Definition & Purpose

  • Pelletization produces small, spherical, free‑flowing particles (200–1500 µm) used for controlled or tailored release.

• Key Techniques

  1. Extrusion–Spheronization:

     • Steps: Wet massing → extrusion to form cylinders → spheronization to round pellets → drying and sieving.

     • Advantages: Uniform size/shape; good load capacity.

  2. Layered Pellet Formation (Nonpareils):

     • Starter Cores: Sugar or microcrystalline cellulose seeds.

     • Drug Layering: API solution or suspension sprayed onto cores in a pelletizer or coating pan.

     • Coating/Seal Coating: Functional coats applied for modified release.

  3. Hot Melt Pelletization:

     • Principle: Melt binder mixed with API → extruded and solidified → spheronized.

     • Advantages: Solvent‑free, gentle for moisture‑sensitive drugs.

• Applications

  • Combine pellets with different release profiles in a single capsule or tablet.

  • Mask taste/odor and improve flow properties.

• Quality Control Tests

  • Size Distribution: Laser diffraction or sieve analysis for uniformity.

  • Sphericity & Surface Morphology: Microscopy to ensure roundness and smooth finish.

  • Drug Content Uniformity: Assay of individual pellets.

  • Dissolution/Release Kinetics: Validate immediate vs. sustained‑release behavior.

Key Takeaways for Exams

1. Differentiate hard vs. soft gelatin capsules by shell composition, fill type, and manufacturing process.

2. List the main filling techniques for hard gelatin capsules and associated QC parameters.

3. Explain extrusion–spheronization steps and how they influence pellet characteristics.

4. Describe how pellet layering enables multiparticulate modified‑release formulations.

5. Identify critical quality tests for capsules and pellets, and interpret their acceptance criteria.