Overview
- Physical behaviour = drug ka physical nature — particle size, solubility, solid state, flow, viscosity, etc. Yeh decide karta hai formulation ka delivery, stability aur patient acceptance.
- Chemical behaviour = drug ka chemical reactions aur degradation (hydrolysis, oxidation, photolysis, racemization). Yeh shelf-life aur safety pe effect dalta hai.
- Rationale of formulation = kyun koi particular dosage form, excipient, or process choose kara gaya — therapeutic goal + stability + manufacturability + patient factors.
- Compounding techniques = practical methods — powders, capsules, tablets (granulation), suspensions, emulsions, ointments, parenterals, lyophilization, etc.
Physical behaviour — ek-ek point (samjhaasan + implication)
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Physical state — Solid / Liquid / Gas / Paste
- Solid forms: crystalline vs amorphous.
- Implication: Amorphous → higher solubility but less stable (tends to recrystallize). Crystalline → stable but lower solubility.
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Polymorphism
- Ek hi molecule ke different crystal forms. Har polymorph ka solubility, melting point, stability alag.
- Example: Sulfathiazole polymorphs.
- Why care? Patent, stability, dissolution change ho sakta hai.
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Particle size and surface area
- Chhota particle → larger surface area → faster dissolution (Noyes-Whitney).
- Techniques to change: micronization, milling, spray drying.
- Trade-off: Too fine → aggregation, poor flow, dust hazard.
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Solubility & dissolution rate
- Solubility = max drug dissolved in solvent; dissolution = rate of going into solution.
- Implication: Poorly soluble drugs → low bioavailability (BCS Class II). Use micronization, salt formation, cyclodextrin complexation, lipid systems.
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Partition coefficient (log P) & lipophilicity
- Affects membrane permeation. High log P → good membrane crossing but poor aqueous solubility.
- Formulation balance: co-solvents, surfactants, lipid carriers.
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pKa and ionization
- Drug ionization depends on pH → solubility changes. Weak acids/bases show pH-dependent solubility.
- Implication: For oral liquids, adjust pH for max solubility (within safety).
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Hygroscopicity & deliquescence
- Water uptake from air. Leads to clumping, dissolution, stability loss.
- Control: use desiccants, choose non-hygroscopic excipients, package tightly.
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Flow properties (angle of repose, Carr’s index)
- Powder flow affects mixing, tableting, capsule filling.
- Fixes: glidants (colloidal silica), granulation.
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Compressibility & compactibility
- Kitna pressure se tablet banega aur strength kya hogi.
- Approach: Direct compression vs granulation; binders adjust.
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Viscosity & rheology (liquids/semisolids)
- Viscosity affects sprayability, pourability, release rate. Thixotropy = shear-thinning (useful in gels).
- Excipients: HPMC, carbomer, xanthan.
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Wetting & surface energy
- For suspensions, wetting of drug particles by vehicle is crucial. Wetting agents (surfactants) needed for hydrophobic drugs.
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Density & tapped density
- Important for uniform filling of capsules/tablets.
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Porosity
- Affects dissolution and stability of tablets.
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Light sensitivity & photostability
- Some drugs degrade on light exposure → amber containers, opaque packaging.
Chemical behaviour — degradation pathways & control (pointwise)
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Hydrolysis
- Esters, amides, lactams often hydrolyze. Water + pH accelerates.
- Control: choose dry formulation (powder), use aprotic solvents, pH control, lyophilize, use prodrug/salt.
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Oxidation
- Phenols, sulfides, catechols oxidize; metals catalyze.
- Control: antioxidants (ascorbic acid, BHT), chelators (EDTA), oxygen-free packaging (nitrogen flush).
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Photolysis
- UV/visible light causes bond breakage.
- Control: amber glass, light barrier.
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Polymerization / degradation via radicals
- Peroxides in PEG can initiate. Avoid peroxide-forming excipients, test peroxides.
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Racemization & epimerization
- Chirality change can reduce activity or increase toxicity. pH and temperature dependent.
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Maillard reaction (sugar + amine)
- Reducing sugars + primary amines → browning + instability (takes place in syrups with amino drugs).
- Control: use non-reducing sweeteners (sorbitol), avoid lactose if reactive.
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Kinetics: zero-order vs first-order
- Zero-order: constant mg lost per time. First-order: percent loss per time.
- Use: shelf-life (t90) calculation, stability modeling using Arrhenius for temperature effect.
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Environmental factors
- Temperature ↑, humidity ↑, light, oxygen all accelerate degradation.
Rationale underlying formulation — “why we choose what we choose”
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Therapeutic objectives
- Rapid onset vs sustained release; local action vs systemic. Example: nasal spray for local congestion vs oral SR for chronic therapy.
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Route of administration
- Oral, topical, parenteral, inhalation, rectal — har route ke constraints: sterility, particle size, viscosity, isotonicity.
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Dose & potency
- High-dose drug needs larger tablet; low-dose potent drug requires content uniformity, blending sensitivity, perhaps layering or microencapsulation.
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Biopharmaceutic needs (BCS)
- BCS I–IV guide strategy: e.g., Class II (low solubility, high permeability) → enhance solubility; Class III (high solubility, low permeability) → permeation enhancers.
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Patient acceptability
- Taste masking (bitterness), ease of swallowing (orodispersible), dosing frequency (compliance), pediatric/geriatric forms (syrups, suspensions).
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Stability & shelf-life
- Choose excipients and packaging to meet shelf-life targets (ICH stability testing).
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Manufacturability & cost
- Simpler process may be cheaper and more robust; avoid overcomplex design if unnecessary.
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Regulatory & safety
- Use of GRAS excipients, impurity limits, preservative and preservative efficacy testing, aseptic standards.
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Excipient functions — practical list
- Fillers/Diluents: lactose, microcrystalline cellulose (MCC).
- Binders: PVP, starch, HPMC.
- Disintegrants: croscarmellose sodium, sodium starch glycolate.
- Lubricants: magnesium stearate (overuse → reduces tablet hardness).
- Glidants: colloidal silicon dioxide.
- Surfactants/Wetting agents: Tween 80, SLS.
- Preservatives: parabens, benzalkonium chloride (for multi-dose liquids).
- Antioxidants: ascorbic acid, sodium metabisulfite.
- Buffers: citrate, phosphate systems.
- Tonicity agents: NaCl for parenterals/ophthalmics.
- Film coatings & enteric coatings: HPMC, Eudragit.
- Complexing agents: cyclodextrins (solubility/taste masking).
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Formulation strategies for common problems
- Poor solubility → salt formation, co-solvents, cyclodextrin, lipid formulation, nanoparticle formulation.
- Bad taste → coating, microencapsulation, flavoring agents, cyclodextrins.
- Short half-life → controlled release matrix, osmotic pump, prodrug.
Compounding techniques — practical step-by-step & tips (per dosage form)
Pehle safety note: Sterile parenteral compounding must be done in licensed facilities with trained staff. Non-sterile compounding is hospital/pharmacy level and should follow standards (USP <795>/<797>, local rules).
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Powders (bulk & divided)
- Techniques: trituration (mortar-pestle), levigation (liquid wetting to reduce particle size), geometric dilution (to mix small drug with large excipient uniformly).
- Tip: always add drug to diluent in small increments (geometric) for uniformity.
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Capsules
- Steps: determine dose per capsule → choose capsule size → mix drug + filler via geometric dilution → fill manually or with capsule filler.
- Tip: poor flowing powders → add glidant; sticky → use talc (sparingly).
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Tablets
- Direct compression: when powder compressibility is good.
- Wet granulation: mix API with binder solution → granulate → dry → mill → lubricate → compress.
- Dry granulation: roll compaction / slugging (for moisture/heat sensitive drugs).
- Troubleshoot: capping — reduce granule friability, adjust binder; sticking — adjust lubricant, punch polish.
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Suspensions
- Goal: uniformly dispersed solid in liquid, redispersible.
- Steps: wet the powder (use wetting agent like glycerin, alcohol) → prepare vehicle with suspending agent (xanthan, CMC) → add drug slowly with agitation → adjust pH, preservative.
- Important: control particle size (micronize if needed).
- Flocculated systems settle fast but redispersible; deflocculated settle slowly but may cake.
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Emulsions (O/W or W/O)
- HLB concept: choose emulsifier by required Hydrophile/Lipophile Balance.
- Method: mix oil + lipophilic surfactant; water + hydrophilic surfactant; pre-emulsify → high shear homogenization → check droplet size.
- Problems: creaming → increase viscosity; coalescence → poor emulsifier or inadequate homogenization.
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Solutions & Syrups
- Solubilization: cosolvents (ethanol, propylene glycol), surfactants, pH adjustment.
- Preservation: multi-dose liquids need preservatives if aqueous.
- Taste: use flavors, sweeteners; for diabetics use non-sugar sweeteners.
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Ointments / Creams / Gels
- Levigation to incorporate solids into base.
- Fusion method — melt fats/waxes, cool with stirring and add aqueous phase (for creams).
- Gels: disperse polymer (carbomer) in water, neutralize to gel.
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Suppositories
- Fusion & molding: melt base (cocoa butter or PEG blend), add drug (consider displacement value), pour into molds.
- Cooling: controlled to avoid cracking.
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Sterile Parenterals (IV/IM/SC)
- Aseptic technique: garbing, LAF hood, sterilized glassware.
- Sterilization: terminal (autoclave for heat-stable) or sterile filtration (0.22 µm) for heat-labile.
- Checks: particulate matter, endotoxin testing (LAL), sterility tests.
- Note: compounding sterile injectables requires strict protocols and environmental monitoring.
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Lyophilization (Freeze-drying)
- When: heat/aqueous sensitive biologics.
- Steps: freeze → primary drying (sublimation) → secondary drying (desorption).
- Outcome: dry cake, reconstitute before use.
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Advanced: Nanoparticles / Liposomes / Solid dispersions
- Techniques: microfluidization, spray drying, hot-melt extrusion, solvent evaporation.
- Use: enhance solubility, targeted delivery.
Calculations & practical examples (short)
- Geometric dilution example: if drug 1 g to be mixed into 99 g excipient → mix 1 g drug + 1 g diluent → then add 2 g → then 4 g … doubling until all diluent used.
- Preparing 100 mL 1% w/v solution: 1% w/v = 1 g per 100 mL → weigh 1.0 g API, dissolve to 100 mL.
- Capsule fill weight: determine drug dose (mg), choose appropriate excipient to reach desired bulk fill; use bulk density to calculate fill volume.
Stability testing & documentation
- Forced degradation studies → see which degradation pathways relevant (acid/base, oxidative, thermal, photolytic).
- Shelf-life (t90) using kinetics + Arrhenius model for temp effect.
- ICH stability conditions (accelerated, long term) → required for regulatory filing.
- Batch record & master formula → document exact process, QC tests, sampling, release criteria.
- Beyond-Use Date (BUD) for compounded preparations (follow USP/local guidelines) — often much shorter than manufactured products.
8) Packaging & container considerations
- Glass (Type I borosilicate) for parenterals; plastics for convenience but check extractables/leachables.
- Amber vs clear for light sensitive drugs.
- Desiccant for hygroscopic formulations.
- Single-dose vs multi-dose — multi-dose liquids need preservatives.
Common problems & fixes (quick troubleshooting)
- Tablet capping: check drying, binder, punch issues.
- Sticking/ Picking: reduce binder on surface, use anti-adhesive coat.
- Emulsion breaking: increase emulsifier, homogenize better, check phase ratio.
- Suspension caking: use flocculating agents (electrolytes or polymers), increase viscosity.
- Ointment gritty: insufficient levigation; pass through finer mortar/pestle.
Practical checklist before compounding (must do)
- Confirm prescription & dose.
- Check drug stability in chosen vehicle & compatibilities (API-excipient).
- Calculate amounts precisely; plan geometric dilution if needed.
- Prepare equipment sterile/clean as appropriate.
- Choose correct container & label (storage instructions).
- Document batch record & label BUD.
- QC checks: appearance, pH, viscosity, assay if possible.
Key takeaways — short & practical
- Physical properties (particle size, polymorph, solubility) control how drug behaves; chemical properties control how long it survives.
- Excipients aren’t “inactive” — they shape release, stability, and acceptability.
- Formulation = compromise: stability vs bioavailability vs patient acceptability vs manufacturability.
- Good formulation uses science (QbD, DoE), not guesses.
- Safety & sterility rules are non-negotiable for parenterals.
- Always document — reproducibility is king.