B Pharmacy Sem 2: Pharmaceutics I

Subject 3. Pharmaceutics I

1. Introduction to Dosage Forms & Pharmaceutical Calculations
2. Pre formulation Studies (Solubility, Partition Coefficient)
3. Particle Size Reduction & Surface Area Analysis
4. Powder Flow Properties & Granulation Techniques
5. Dispersion Systems (Suspensions & Emulsions)
6. Tablet & Capsule Technology
7. Good Manufacturing Practices (GMP) & Novel Drug Delivery Overview

Unit 1: Introduction to Dosage Forms & Pharmaceutical Calculations

This unit introduces the various categories of dosage forms used to deliver drugs safely and effectively, and the essential calculations required for preparing and standardizing pharmaceutical formulations.

1.1 Dosage Forms: Definition & Classification

Dosage Form: the physical form in which a drug is produced and administered, designed for proper dosing, stability, and patient acceptability.

Key Considerations

• Route: oral, parenteral, topical, pulmonary, etc.

• Release Profile: immediate, sustained, controlled, targeted.

• Patient Factors: age, ability to swallow, compliance, local vs. systemic action.

1.2 Pharmaceutical Calculations: Core Concepts

Accurate calculations ensure each dosage form contains the correct amount of active drug and excipient.

1.2.1 Expression of Strength

1.2.2 Dilution & Allegation

• Dilution Formula:

  C1V1=C2V2 C_1V_1 = C_2V_2C1​V1​=C2​V2​

  e.g., To prepare 500 mL of 0.9 % NaCl from a 5 % stock:

  V1=0.9×5005=90  mL (stock),  V2=500 mL final V_1 = \frac{0.9\times500}{5} = 90\;\text{mL (stock)},\; V_2=500\text{ mL final}V1​=50.9×500​=90mL (stock),V2​=500 mL final

• Alligation Method: blending two solutions of different strengths to achieve a target strength.

1.2.3 Dosage Calculations

• Body‑weight–based dosing:

  Dosepatient=Dosekg×Patient weight (kg) \text{Dose}_\text{patient} = \text{Dose}_\text{kg} \times \text{Patient weight (kg)}Dosepatient​=Dosekg​×Patient weight (kg)

• Body‑surface area (BSA) dosing:

  BSA =Wt (kg)×Ht (cm)3600 \text{BSA} = \sqrt{\frac{\text{Wt (kg)} \times \text{Ht (cm)}}{3600}}BSA =3600Wt (kg)×Ht (cm)​​

1.3 Calculation of Dosage Form Components

When formulating a solid or liquid dosage form, calculate each ingredient:

1. Active Drug Quantity: based on prescribed strength and dose.

2. Diluent/Filler: to achieve desired bulk (e.g., lactose in tablets).

3. Vehicle: volume of solvent for solutions/suspensions.

4. Excipients: binders, disintegrants, preservatives—expressed as % w/w or % w/v.

1.4 Examples & Practice Problems

1. Tablet Blend:

   • Desired: 250 mg API per tablet, 100 000 tablets

   • Total API = 0.25 g × 100 000 = 25 kg

   • If filler = 75 % w/w of batch, calculate filler mass.

2. Syrup Preparation:

   • 30 % w/v sucrose syrup, final volume 1 L

   • Sucrose required = 300 g; water qs to 1 L.

3. IV Infusion:

   • Order: 1 g drug in 250 mL D5W over 30 min

   • Concentration = 1 g/250 mL = 4 mg/mL; infusion rate = 250 mL/30 min ≈8.3 mL/min.

1.5 Key Points for Exams

• Know strength expressions (% w/v, ratio, molarity).

• Apply C₁V₁ = C₂V₂ for dilutions accurately.

• Use alligation to mix strengths.

• Perform dose calculations based on weight and BSA.

• Calculate component masses/volumes for batch formulations.

Unit 2: Pre‑formulation Studies (Solubility & Partition Coefficient)

This unit covers the preliminary evaluation of a drug substance’s physicochemical properties—particularly solubility and lipophilicity—which guide formulation design, selection of suitable dosage forms, and strategies for bioavailability enhancement.

2.1 Importance of Pre‑formulation

• Objective: characterize the API to predict its behavior in dosage forms and in vivo

• Outcomes: selection of salt or polymorph, choice of excipients, design of solubility‑enhancement techniques

2.2 Solubility

2.2.1 Definition

• Solubility: maximum amount of solute that dissolves in a given solvent at a specified temperature and pressure, expressed as mg/mL or g/100 mL.

2.2.2 Factors Affecting Solubility

2.2.3 Measurement Methods

• Shake‑Flask Method: equilibrate excess drug with solvent; analyze supernatant (UV–Vis, HPLC)

• Turbidimetric Method: monitor cloud point or turbidity increase as solubility limit is exceeded

• Potentiometric Titration: detect dissolution via pH or ion‑selective electrodes

• Thermodynamic Solubility: assess at equilibrium, correcting for undissolved particles

2.2.4 Classification of Solubility (USP)

• Very soluble: < 1 part solvent per 1 part solute

• Freely soluble: 1–10 parts solvent per 1 part solute

• Soluble: 10–30 parts solvent per 1 part solute

• Sparingly soluble: 30–100 parts solvent/solute

• Slightly soluble: 100–1 000 parts

• Very slightly soluble: 1 000–10 000 parts

• Practically insoluble: > 10 000 parts

2.3 Partition Coefficient

2.3.1 Definition

• Partition Coefficient (P): ratio of concentrations of a non‑ionized compound between two immiscible solvents (typically octanol and water):

  P=[Drug]octanol[Drug]water P = \frac{[\text{Drug}]_{\text{octanol}}}{[\text{Drug}]_{\text{water}}}P=[Drug]water​[Drug]octanol​​

• log P: logarithmic form; measures lipophilicity.

2.3.2 Distribution Coefficient (log D)

• Accounts for ionized and non‑ionized species at a given pH:

  D=total drug in octanoltotal drug in water D = \frac{\text{total drug in octanol}}{\text{total drug in water}}D=total drug in watertotal drug in octanol​

• log D varies with pH for ionizable drugs.

2.3.3 Significance in Formulation

• Permeability: intermediate log P (1–3) favors membrane crossing

• Absorption & Distribution: high lipophilicity improves membrane partitioning but may reduce solubility

• Stability & Metabolism: very lipophilic drugs may exhibit high protein binding and extensive metabolism

2.3.4 Measurement Techniques

• Shake‑Flask Method: equilibrate drug between octanol and buffer; analyze both phases

• Chromatographic Methods: HPLC retention times correlate with log P (“capacity factor” approach)

• Computational Prediction: in silico tools estimate P from molecular structure

2.4 Applications in Formulation Design

• Salt Selection: convert poorly soluble free base/acid to a more soluble salt form

• Polymorph Screening: identify form with optimal solubility and stability

• Solubilization Strategies:

  • Solid Dispersions (e.g., with PEG, PVP)

  • Cyclodextrin Complexation

  • Lipid‑based Systems (e.g., self‑emulsifying drug delivery systems)

• Balancing Solubility & Permeability: use pH modifiers, surfactants, or cosolvents to achieve desired dissolution and absorption profiles.

2.5 Key Points for Exams

• Define solubility and list major factors influencing it.

• Describe shake‑flask and turbidimetric methods for solubility determination.

• State the difference between log P and log D, and their relevance.

• Explain how salt formation and solid dispersions enhance solubility.

• Recognize the “solubility‑permeability” balance in oral drug design.

Unit 3: Particle Size Reduction & Surface Area Analysis

This unit examines how reducing and controlling particle size—and measuring specific surface area—impacts drug dissolution, bioavailability, stability, and processing characteristics.

3.1 Importance of Particle Size & Surface Area

• Dissolution Rate: according to the Noyes–Whitney equation, rate ∝ surface area

• Bioavailability: smaller particles dissolve faster → improved absorption for poorly soluble drugs

• Content Uniformity: uniform particle size ensures consistent dosing

• Flow & Compression: influences powder behavior in hopper, die-filling, tablet compactibility

• Sedimentation & Suspension Stability: fine particles remain suspended longer

3.2 Particle Size Classification

3.3 Methods of Particle Size Reduction

3.3.1 Mechanical Milling

• Ball Mill: tumbling action of balls breaks particles; suitable for large batches

• Hammer Mill: high‑speed rotating hammers impact particles; coarse to fine range

• Roller Mill: compression between rollers; good for brittle materials

3.3.2 Air‑Classifying (Fluid Energy) Milling

• High‑velocity steam or air jets collide particles → ultrafine powders (down to submicron)

• Advantages: narrow size distribution, minimal heat buildup

3.3.3 High‑Pressure Homogenization

• Suspended drug forced through narrow orifice under high pressure → cavitation and shear

• Produces nanoparticles and nanosuspensions; used for poorly soluble APIs

3.3.4 Cryogenic Grinding

• Drug frozen with liquid nitrogen → brittle state → easier micronization

• Minimizes thermal degradation for heat‑sensitive compounds

3.4 Particle Size Analysis Techniques

• Key Parameters:

  • d₁₀, d₅₀ (median), d₉₀: percentiles indicating that 10 %, 50 %, or 90 % of particles are below the given size

  • Span: (d₉₀ – d₁₀)/d₅₀, measures distribution width

3.5 Surface Area Measurement

• BET Gas Adsorption: measures amount of gas adsorbed on surface → calculates specific surface area (m²/g)

• Mercury Porosimetry: intrusion of mercury at controlled pressure → pore size distribution and surface area for porous particles

• Calculated from Particle Size: assuming spherical particles:

  Surface area (m²/g)=6ρ×dmean \text{Surface area (m²/g)} = \frac{6}{\rho \times d_{\text{mean}}}Surface area (m²/g)=ρ×dmean​6​

  where ρ = true density, dₘₑₐₙ = mean particle diameter

3.6 Effects on Formulation & Processing

• High Surface Area:

  • ↑ dissolution but also ↑ hygroscopicity and potential for oxidation

  • May require protective coatings or antioxidants

• Particle Size & Flow:

  • Very fine powders (d₅₀ < 50 µm) tend to be cohesive; may need glidants (e.g., colloidal silica)

  • Granulation often used to improve flow of fine powders

• Inhalation Therapy:

  • Optimal aerodynamic diameter ~1–5 µm for deep lung deposition

  • Requires precise control via jet milling and cascade impactor testing

3.7 Key Points for Exams

• Describe major milling methods (ball, fluid energy, homogenization, cryogenic) and when to use each.

• State common particle size analysis techniques and their applicable ranges.

• Explain how surface area affects dissolution and stability.

• Define d₁₀, d₅₀, d₉₀ and span for particle distributions.

• Discuss formulation strategies (glidants, coatings, granulation) for powders with poor flow or high hygroscopicity.

Unit 4: Powder Flow Properties & Granulation Techniques

This unit examines how powders behave during handling and processing, and how granulation improves flow, uniformity, and compressibility for solid dosage forms.

4.1 Powder Flow Properties

4.1.1 Definitions

• Flowability: the ease with which powder particles move relative to each other.

• Cohesion vs. Adhesion: cohesive powders stick to themselves; adhesive powders stick to equipment surfaces.

4.1.2 Factors Affecting Flow

4.1.3 Flow Measurement

• Angle of Repose:

  tan⁡(θ)=heightradius \tan(θ) = \frac{\mathit{height}}{\mathit{radius}}tan(θ)=radiusheight​

  • Excellent flow: θ < 25°; Poor flow: θ > 40°

• Carr’s Compressibility Index (CI):

  CI=ρtapped−ρbulkρtapped×100 \text{CI} = \frac{\rho_{\rm tapped} – \rho_{\rm bulk}}{\rho_{\rm tapped}} \times 100CI=ρtapped​ρtapped​−ρbulk​​×100

  • CI < 15 %: good flow; > 25 %: poor flow

• Hausner Ratio (HR):

  HR=ρtappedρbulk \text{HR} = \frac{\rho_{\rm tapped}}{\rho_{\rm bulk}}HR=ρbulk​ρtapped​​

  • HR < 1.25: good flow; > 1.4: poor flow

4.2 Granulation Techniques

4.2.1 Objectives of Granulation

• Improve flow and prevent segregation

• Enhance compressibility for tablet formation

• Reduce dust generation for safety

4.2.2 Wet Granulation

1. Mixing: blend API with dry excipients.

2. Binder Addition: spray or knead with granulating fluid (water, ethanol, PVP solution).

3. Granule Formation: pass wet mass through sieve to desired size.

4. Drying: tray or fluid‑bed until moisture content ~1–2 %.

5. Sizing: mill dried granules to uniform size.

Advantages: uniform granules, high hardness tablets
Limitations: heat/moisture may degrade sensitive drugs

4.2.3 Dry Granulation

• Slugging: compress powder into large tablets (slugs), then mill into granules

• Roller Compaction: powder passed between rollers under pressure to form ribbons, then milled

Advantages: no solvents or heat; suitable for moisture‑sensitive drugs
Limitations: higher fines; may require additional sizing

4.2.4 Direct Compression

• Blend API with directly compressible excipients (e.g., microcrystalline cellulose, lactose) and compress.

• Advantages: simplest, least steps, cost‑effective

• Limitations: requires good flow and compressibility; not suitable for low‑dose or poor‑flow APIs

4.3 Binder & Excipient Selection

4.4 Equipment Used

• High‑Shear Mixers/Granulators: rapid distribution of binder; large‑scale production

• Fluid‑Bed Granulators: simultaneous granulation and drying; good control of moisture

• Roller Compactors: continuous dry granulation

• Slugging Presses: for small‑scale dry granulation

4.5 Quality Control of Granules

• Moisture Content: ensure optimal for compressibility without caking

• Particle Size Distribution: sieving or laser diffraction to target 150–500 µm

• Flow Properties: repeat angle of repose, CI, HR measurements

• Granule Strength: friability testing (should be < 2 % weight loss)

4.6 Key Points for Exams

• Calculate angle of repose, Carr’s index, and Hausner ratio from bulk/tapped densities.

• Compare wet vs. dry vs. direct granulation: steps, pros/cons.

• Select appropriate binders and excipients for each granulation method.

• Describe major granulation equipment and their roles.

• Outline quality tests for granules (moisture, size, flow, friability).

Unit 5: Dispersion Systems (Suspensions & Emulsions)

This unit examines dispersed dosage forms in which one phase is distributed throughout another. You’ll learn formulation principles, preparation methods, evaluation tests, and stability considerations for suspensions and emulsions.

5.1 Definitions & Classification

• Dispersion System: two‑phase system where one phase (dispersed) is distributed in another (continuous).

  • Suspension: solid particles dispersed in a liquid.

  • Emulsion: liquid droplets dispersed in another immiscible liquid.

5.2 Suspensions

5.2.1 Formulation Components

• Active Ingredient: micronized or coarse API.

• Vehicle: aqueous (syrup base) or non‑aqueous (oil).

• Suspending Agents: e.g., methylcellulose, xanthan gum—increase viscosity to slow sedimentation.

• Wetting Agents: e.g., polysorbate 80, sodium lauryl sulfate—to displace air and allow water to penetrate particles.

• Flocculating Agents: e.g., electrolytes (Al³⁺ salts), surfactants—to form loose aggregates for easy redispersion.

• Preservatives: e.g., sodium benzoate, parabens—to prevent microbial growth.

5.2.2 Preparation Methods

1. Dry Wetting: triturate API with wetting agent, then levigate with vehicle to form uniform paste.

2. Particle Size Adjustment: milling or sieving to desired range (10–50 µm).

3. Addition of Suspending Agent: in portion of vehicle to form viscous base.

4. Final Volume Adjustment & Homogenization: add remaining vehicle, stir or homogenize to uniformity.

5.2.3 Evaluation Tests

5.2.4 Stability Considerations

• Sedimentation vs. Caking: formulate to achieve reversible flocculation.

• Microbial Growth: include effective preservative system.

• pH Drift: monitor, may alter API solubility or vehicle viscosity.

5.3 Emulsions

5.3.1 Types of Emulsions

• Oil-in-Water (O/W): oil droplets in an aqueous phase; used for oral and topical hydrophilic preparations.

• Water-in-Oil (W/O): water droplets in oil; used for water‑resistant topical applications.

• Multiple Emulsions (W/O/W, O/W/O): complex; controlled release.

5.3.2 Formulation Components

• Oil Phase: vegetable oils (olive, castor), mineral oil, liquid paraffin.

• Aqueous Phase: water or buffer.

• Emulsifying Agents:

  • Low HLB (3–6) for W/O (e.g., sorbitan monooleate).

  • High HLB (8–18) for O/W (e.g., polysorbate 80).

• Auxiliary Stabilizers: co‑emulsifiers (lecithin), viscosity modifiers (carbomers).

• Preservatives: water‑phase antimicrobials (e.g., methylparaben).

5.3.3 Preparation Methods

1. Dry Gum (Continental) Method: triturate oil + gum (e.g., acacia) 4:2 by weight, add water all at once → primary emulsion; churn in remaining water.

2. Wet Gum (English) Method: triturate gum with water first, then add oil slowly with triturating to form emulsion.

3. Phase Inversion: adjust temperature or composition to invert type (e.g., O/W to W/O).

4. High‑Shear Homogenization: rotor–stator devices for fine droplets (1–10 µm).

5.3.4 Evaluation Tests

5.3.5 Stability Considerations

• Creaming: reversible; minimize by small droplet size and appropriate viscosity.

• Coalescence & Breaking: irreversible; prevented by strong interfacial film (good emulsifier choice).

• Ostwald Ripening: growth of larger droplets; minimize by adding ripening inhibitors (e.g., long-chain oils).

5.4 Key Points for Exams

• Differentiate suspension vs. emulsion, and list their formulation components.

• Explain the roles of wetting agents, suspending agents, and emulsifiers.

• Describe classic gum methods and homogenization for emulsion preparation.

• Define sedimentation volume, creaming, and interpret their values.

• Discuss major stability issues (caking, coalescence) and strategies to mitigate them.

Unit 6: Tablet & Capsule Technology

This unit explores the design, formulation, manufacturing, and evaluation of the two most widely used oral solid dosage forms—tablets and capsules.

6.1 Tablets

6.1.1 Definition & Advantages

• Tablet: a solid dosage form prepared by compressing powder or granules containing active drug and excipients.

• Advantages: accurate dosing, ease of manufacture, stability, patient compliance, multiple release profiles.

6.1.2 Types of Tablets

6.1.3 Tablet Excipients

6.1.4 Manufacturing Processes

1. Granulation (optional): wet or dry to improve flow and compressibility.

2. Blending: mix API with excipients uniformly.

3. Compression: rotary or single‑punch tablet press applies force to form tablets.

4. Coating: film or sugar coating applied in coating pans or fluid‑bed coaters.

6.1.5 Evaluation of Tablets

6.2 Capsules

6.2.1 Definition & Advantages

• Capsule: a solid dosage form in which the drug is enclosed within a shell, usually gelatin or HPMC.

• Advantages: easy to swallow, taste‑masking, flexible dosing, suitable for powders and granules.

6.2.2 Types of Capsules

6.2.3 Capsule Excipients & Fillers

6.2.4 Filling Processes

• Hard Capsules:

  1. Separation of cap and body.

  2. Dosing of powder/granules into body (dosator, tamping pins, or vacuum-immersion).

  3. Rejoining cap and body.

• Soft Capsules: continuous rotary die process where gelatin ribbon envelopes fill material.

6.2.5 Evaluation of Capsules

6.3 Key Points for Exams

• Compare tablet vs. capsule advantages and limitations.

• List common excipients and their functions in tablets and capsules.

• Describe manufacturing steps for tablet compression and capsule filling.

• State major quality tests (weight variation, hardness/disintegration, dissolution).

• Recognize special tablet types (enteric-coated, sustained-release) and capsule variations (hard vs. soft).

Unit 7: Good Manufacturing Practices (GMP) & Novel Drug Delivery Overview

This unit introduces the regulatory framework ensuring product quality and safety (GMP) and provides a survey of emerging drug delivery technologies that enhance efficacy, targeting, and patient compliance.

7.1 Good Manufacturing Practices (GMP)

7.1.1 Definition & Purpose

• GMP: A system of standards, procedures, and documentation to ensure pharmaceutical products are consistently produced and controlled to quality standards appropriate to their intended use.

7.1.2 Key Components of GMP

7.1.3 Regulatory Guidelines

• International: ICH Q7 (API GMP), WHO GMP

• USA: 21 CFR Parts 210–211

• Europe: EudraLex Volume 4

• Key Principles: risk‑based approach, data integrity (ALCOA+), continuous improvement

7.1.4 Documentation Examples

• Master Batch Record: detailed formula and manufacturing instructions

• Batch Production Record: actual data recorded during production

• Deviation Report: investigation of any process departures

• Change Control Form: management of changes impacting quality

7.2 Overview of Novel Drug Delivery Systems (NDDS)

7.2.1 Rationale for NDDS

• Improve bioavailability of poorly soluble drugs

• Achieve controlled or targeted release

• Enhance patient compliance (e.g., fewer doses)

• Reduce side effects by site-specific delivery

7.2.2 Major NDDS Categories

7.2.3 Selection Criteria for NDDS

• Physicochemical Properties: solubility, stability, molecular weight

• Route of Administration: oral, parenteral, transdermal, pulmonary, mucosal

• Target Site: systemic vs. local; passive (EPR effect) vs. active (ligand-mediated) targeting

• Release Profile: burst vs. sustained vs. pulsatile

7.2.4 Development Considerations

• Formulation Design: choice of excipients, polymers, surfactants, particle size

• Scale‑up & Manufacturing: reproducible processes (microfluidics, spray‑drying, emulsification)

• Characterization: size distribution (DLS, SEM), zeta potential, encapsulation efficiency, in vitro release

• Regulatory & Safety: immunogenicity, toxicity, stability, sterility (for parenterals)

7.3 Key Points for Exams

• List GMP components and outline documentation requirements.

• Define the purpose of NDDS and classify major system types.

• Compare liposomes vs. polymeric nanoparticles in terms of composition and use.

• Describe basics of transdermal patches and osmotic pumps for controlled release.

• Recognize critical development and regulatory considerations for NDDS.