Liquid and semisolid dosage forms

In short

Liquid dosage forms are preparations in which the drug is dissolved (solutions, syrups, elixirs, linctuses), suspended (suspensions, magmas, gels) or emulsified (emulsions, lotions) in a vehicle; semisolids are ointments, creams, pastes, gels, poultices and suppositories applied to skin or mucosa. They matter because they allow flexible dosing for children and the elderly, deliver drugs locally with little systemic exposure, and dominate the OTC shelf in India (cough syrups, antacid suspensions, antifungal creams). The topic is examined in Pharmaceutics (monophasic and biphasic liquids, semisolids, suppositories) in every B.Pharm syllabus under the PCI model curriculum, and in GPAT, NIPER JEE and D.Pharm exams. In interviews at Cipla, Sun Pharma, Dr Reddy's, Zydus, Alkem, Mankind, Himalaya and Emami, formulation, production and QC roles ask about HLB, flocculation, caking, displacement value and viscosity control. Rheology, preservative efficacy and container-closure choice are the recurring practical problems.

Explained

Monophasic liquids: one-phase solutions

• Solution: a homogeneous, one-phase liquid of solute molecularly dispersed in a solvent; no settling, so no shaking needed, and bioavailability is usually highest among oral forms.
• Syrup: near-saturated sucrose solution, about 66.7% w/w sucrose (simple syrup, IP); self-preserving at that strength because free water is low (low water activity). Sugar-free syrups use sorbitol, mannitol or sucralose for diabetics.
• Elixir: sweetened hydroalcoholic clear liquid (ethanol roughly 5-40%) used for drugs poorly soluble in water; alcohol limits paediatric use.
• Linctus: viscous, sugary liquid sipped slowly to soothe the throat (codeine linctus, non-codeine antitussives).
• Mixture: liquid for oral use containing dissolved or suspended drugs, usually freshly prepared and short-dated.
• Draught, drops, gargles, mouthwashes, throat paints (glycerin-based, viscous), nasal drops, ear drops (glycerin/propylene glycol vehicles), enemas, douches - route-specific liquids.
• Spirits (alcoholic/hydroalcoholic solutions of volatiles), aromatic waters (saturated aqueous solutions of volatile oils), tinctures (alcoholic extracts of crude drugs), extracts and infusions/decoctions - galenicals still monographed in IP and widely used in Ayurvedic manufacture.
• Solubility aids: cosolvency (ethanol, glycerin, propylene glycol, PEG 400), pH adjustment and salt formation, surfactant micellar solubilisation, complexation (cyclodextrins), hydrotropy (sodium benzoate, caffeine).

Additives and stability of liquid orals

• Vehicles: purified water IP (the commonest), aromatic waters, hydroalcoholic blends, glycerin, fixed oils for oily preparations.
• Sweeteners: sucrose, sorbitol, saccharin sodium, aspartame (contraindicated in phenylketonuria), sucralose, liquid glucose.
• Preservatives: methylparaben + propylparaben (commonly 0.18% + 0.02%), sodium benzoate (needs pH below about 5 to give undissociated benzoic acid), potassium sorbate, benzalkonium chloride (topical/ophthalmic), chlorocresol, phenylmercuric nitrate. Preservative efficacy depends on unionised fraction, partitioning into oil phase and binding to nonionic surfactants and macromolecules.
• Antioxidants: sodium metabisulphite, sodium sulphite, ascorbic acid for aqueous; BHA, BHT, alpha-tocopherol, propyl gallate for oily; chelating synergists EDTA and citric acid.
• Buffers (citrate, phosphate, acetate), viscosity builders (sodium CMC, tragacanth, xanthan gum, acacia), colours permitted under the Food Safety and Standards rules and Drugs and Cosmetics Rules, flavours matched to taste (menthol-mint for salty, citrus for sour, cocoa-vanilla for bitter).
• Degradation routes: hydrolysis (esters, amides), oxidation, photolysis, microbial spoilage, pH-driven precipitation; controlled by pH optimisation, dry-syrup (reconstitutable powder) presentation, amber glass or opaque HDPE, and headspace nitrogen for oxidisable drugs.

Biphasic liquids I: suspensions

• A suspension is a coarse dispersion of insoluble solid (usually 1-50 µm) in a liquid; used for insoluble drugs, bitter drugs (dissolved drug tastes bitter, suspended particles do not), depot injections and X-ray contrast (barium sulphate).
• Settling follows Stokes' law; slowing it needs smaller particles, higher continuous-phase viscosity or a smaller density difference.
• Deflocculated system: particles separate, settle slowly, form a dense, hard cake that cannot be redispersed - the classic failure.
• Flocculated system: particles form loose, porous flocs that settle fast to a high sediment volume, leaving a clear supernatant but redispersing with a shake. Preferred for pharmaceutical stability.
• Controlled flocculation steps: wet and deagglomerate the powder (wetting agent, low HLB-to-moderate surfactant or glycerin levigation) → flocculate with electrolytes (NaCl, KCl, phosphates), surfactants or polymers (CMC, alginate) → add a protective colloid / structured vehicle to suspend the flocs.
• Structured vehicle: a pseudoplastic, thixotropic gel (xanthan, Carbopol, bentonite magma, sodium CMC) that holds flocs at rest but thins on shaking and pouring.
• Zeta potential: flocculation is induced by reducing the absolute zeta potential into the flocculation window (roughly ±20 mV); too little reduction leaves the system deflocculated, which is what cakes, while excess electrolyte can reverse the charge sign and raise the zeta potential again, re-deflocculating the suspension.
• Evaluation: sedimentation volume F = Vu/Vo, degree of flocculation β = F/F∞, redispersibility (number of inversions or mechanical shaker strokes), particle size growth, rheology, pH, assay, deliverable volume, microbial limits.
• Dry syrups (amoxicillin, cefixime) avoid aqueous instability - reconstituted suspension is dated typically 7-14 days refrigerated as per the label.

Biphasic liquids II: emulsions

• An emulsion is a dispersion of one immiscible liquid as globules in another, stabilised by an emulsifying agent; globules are usually 0.1-100 µm.
• Types: o/w (oil in water - most oral emulsions, creams for cosmetic feel, water-washable), w/o (cold creams, emollient preparations), and multiple o/w/o or w/o/w; microemulsions (10-100 nm, thermodynamically stable, clear) and nanoemulsions.
• Identification tests: dilution test (dilutes with the external phase), dye test (water-soluble amaranth colours an o/w continuous phase; Scarlet red/Sudan III colours w/o), conductivity (o/w conducts), filter-paper/fluorescence tests.
• Emulsifiers: natural gums (acacia, tragacanth), proteins (gelatin), carbohydrates (agar, pectin), surfactants (sodium lauryl sulphate anionic, benzalkonium cationic, spans and tweens nonionic), finely divided solids (bentonite, magnesium hydroxide) that sit at the interface, and auxiliary agents (cetyl alcohol, stearic acid).
• HLB system (Griffin): hydrophile-lipophile balance 0-20; roughly 3-6 suits w/o emulsifiers, 7-9 wetting, 8-18 o/w emulsifiers, 13-15 detergents, 15-18 solubilisers. Blends of a high and a low HLB surfactant outperform a single one at the same HLB.
• Preparation: dry gum (continental, 4:2:1 oil:water:gum for fixed oils; 2:2:1 for volatile oils; 4:2:1 adapted for liquid paraffin as 3:2:1) forms the primary emulsion in a dry mortar; wet gum (English) adds oil to gum mucilage; bottle (Forbes) method for volatile oils; nascent soap (in-situ) method for calcium hydroxide-oleic acid lime liniment. Industrially: high-speed stirrers, colloid mills, homogenisers, ultrasonicators.
• Instabilities: creaming (reversible upward/downward concentration of globules), flocculation, coalescence and cracking/breaking (irreversible), phase inversion (electrolyte or temperature change, exceeding about 74% internal phase), Ostwald ripening, microbial attack, rancidity of oils.
• Preservation needs both phases protected: pair a water-soluble paraben with an oil-partitioning one; preservative lost into oil or bound to tweens leaves the aqueous phase unprotected.

Semisolids: ointments, creams, pastes, gels

• Ointment: greasy, anhydrous or low-water semisolid; cream: emulsion semisolid (o/w "aqueous cream", w/o "oily cream"); paste: ointment with a high solid load (20-50%), stiff and protective (zinc oxide paste); gel: a semisolid of liquid trapped in a polymer or inorganic network (Carbopol, HPMC, bentonite); jelly: aqueous, nongreasy; poultice/cataplasm: hot, moist, drawing application; liniment (liquid/oily, rubbed in) and lotion (liquid, patted on) sit between liquids and semisolids.
• Ointment base classes:
• Oleaginous/hydrocarbon - white and yellow soft paraffin, paraffin, plastibase; occlusive, emollient, long contact, no water absorption, difficult to wash off.
• Absorption bases - anhydrous types (wool fat, wool alcohols, beeswax-paraffin blends) that take up water to form w/o systems, and types already containing water (hydrous wool fat/lanolin, cold cream) that absorb still more.
• Water-removable (emulsion o/w) - hydrophilic ointment, emulsifying ointment with water; washable, cosmetically acceptable, can dilute with aqueous solutions.
• Water-soluble - PEG ointment (polyethylene glycol blends); nongreasy, absorbs exudate, no water-insoluble residue.
• Preparation: fusion (melt the higher-melting bases first, stir to congealing, add volatiles last, below about 40 °C) and trituration/incorporation (levigate the powder with a small amount of base or a levigating agent - liquid paraffin for oily bases, glycerin for aqueous - on an ointment slab with a spatula, then geometric dilution). Industrially: planetary/triple-roller mills, vacuum emulsifying mixers, tube-filling and crimping lines.
• Evaluation: drug content, particle size and grittiness, pH (skin products near 4.5-6.5), spreadability, extrudability, viscosity and yield value (cone-and-plate or Brookfield with helipath), in-vitro release through synthetic membrane and permeation through excised skin in Franz diffusion cells, occlusivity, microbial limits, sterility for ophthalmic ointments, metal particles test for ophthalmic ointments, content of tube (minimum fill), stability including phase separation, bleeding and crystal growth.
• Rheology: semisolids are non-Newtonian - plastic (Bingham, with a yield value), pseudoplastic (shear thinning, gums), dilatant (shear thickening, concentrated suspensions) and thixotropic (viscosity recovers with time after shear) - thixotropy is exactly what a good suspension and a good cream need.
• Percutaneous absorption depends on drug concentration and partition coefficient, base (vehicle effect), hydration and occlusion, surface area, skin site and condition, temperature and penetration enhancers (propylene glycol, DMSO, oleic acid, terpenes).

Suppositories and pessaries

• Suppository: solid unit for rectal insertion (adult about 2 g, child 1 g); pessary for vaginal use (about 4 g); bougie for urethral/nasal use. Shapes: torpedo/bullet, cone, globular.
• Uses: local (haemorrhoids, constipation - glycerin/bisacodyl), systemic when the patient is vomiting, unconscious or a child (paracetamol, diazepam, domperidone), partially avoiding hepatic first-pass through lower rectal veins.
• Bases: fatty - theobroma oil (cocoa butter, melts 30-36 °C, shows polymorphism, needs a 20% excess of base in moulds and careful heating below 36 °C), hydrogenated vegetable oils, Witepsol/Massupol; water-soluble - glycero-gelatin (glycerin:gelatin:water, e.g. 70:14:16 for pessaries) and PEG blends (PEG 1000/4000 mixtures, nonmelting, dissolve in rectal fluid, can irritate - moisten before insertion); emulsifying bases.
• Manufacture: melt the base, incorporate drug (levigated or dissolved), pour at a slight excess into a calibrated, lubricated metal mould (soap spirit for fatty bases, liquid paraffin for water-soluble), chill, trim, remove, wrap. Industrially: automatic PVC/aluminium shell forming, filling and sealing.
• Displacement value (DV): the number of parts by weight of drug that displace 1 part of base. Needed because moulds are volume-calibrated but formulae are weighed.
• Evaluation: weight uniformity, melting range/macro melting time, liquefaction or softening time, breaking/crushing strength, dissolution (special apparatus), drug content, uniformity of content.

Key points

• Monophasic vs biphasic - one visible phase (solutions, syrups, elixirs) vs two (suspensions, emulsions); only biphasic ones carry a "shake well" label.
• Syrup IP - 66.7% w/w sucrose; self-preserving by low water activity, not by any added preservative.
• Elixir - clear, sweet, hydroalcoholic; alcohol is a cosolvent, which is why paediatric labels restrict it.
• Stokes' law - sedimentation rate varies with the square of particle diameter and inversely with viscosity.
• Deflocculated = slow settling but hard cake; flocculated = fast settling, high F, easily redispersed - flocculated is the pharmaceutically desirable state.
• Sedimentation volume F = Vu/Vo - F closer to (or above) 1 indicates good suspendability; F > 1 means the floc network has swollen.
• Structured vehicle - thixotropic gel that suspends flocs at rest and thins when shaken.
• HLB - 3-6 for w/o, 8-18 for o/w emulsifiers; HLB of a blend is the weighted mean by weight fraction.
• Dry gum 4:2:1 - oil:water:acacia for fixed oils; 2:2:1 for volatile oils; 3:2:1 for liquid paraffin.
• Creaming is reversible, cracking is not - creaming redisperses on shaking; coalesced globules do not.
• Phase inversion - o/w to w/o from electrolyte, temperature or internal phase above roughly 74%.
• Ointment base families - hydrocarbon, absorption, water-removable, water-soluble; occlusivity falls and washability rises down the list.
• Levigation - wetting and grinding a powder with a small volume of levigating agent to remove grittiness before incorporation.
• Fusion vs trituration - fusion for waxy, high-melting bases; trituration for heat-labile drugs and soft bases.
• Non-Newtonian behaviour - plastic, pseudoplastic, dilatant; thixotropy is time-dependent shear thinning with recovery.
• Displacement value - parts of drug displacing 1 part of base; ignoring it under-doses or overfills the mould.
• Cocoa butter polymorphism - overheating above about 36 °C gives low-melting unstable forms that will not set.
• Regulation - manufacture under the Drugs and Cosmetics Act, 1940 and Rules, 1945, Schedule M revised GMP (strengthened requirements notified in 2023-24, with phased compliance for smaller units), IP monographs from the Indian Pharmacopoeia Commission, CDSCO and State licensing authorities.

Formulas and examples

Example 1 - Stokes' law. Zinc oxide particles of 10 µm (density 5,600 kg/m³) in a vehicle of density 1,010 kg/m³ and viscosity 0.015 Pa·s.

• d² = (10 × 10⁻⁶)² = 1 × 10⁻¹⁰ m²; Δρ = 4,590 kg/m³.
• Numerator = 1 × 10⁻¹⁰ × 4,590 × 9.81 = 4.503 × 10⁻⁶.
• Denominator = 18 × 0.015 = 0.27.
• v = 4.503 × 10⁻⁶ / 0.27 ≈ 1.67 × 10⁻⁵ m/s ≈ 1.67 × 10⁻³ cm/s, i.e. about 6.0 cm per hour.
• Halving the particle size to 5 µm cuts v fourfold to about 1.5 cm/h; raising viscosity to 0.15 Pa·s cuts it tenfold.

Example 2 - sedimentation volume and degree of flocculation. A 100 mL suspension in a measuring cylinder settles to 72 mL after 48 h; a deflocculated control of the same drug settles to 12 mL.

• F = 72/100 = 0.72; F∞ = 12/100 = 0.12.
• β = 0.72/0.12 = 6.0 - the flocculated product has six times the sediment volume, so the sediment is loose and will redisperse.

Example 3 - HLB blending. An o/w emulsion needs HLB 12. Available: Tween 80 (HLB 15.0) and Span 80 (HLB 4.3); total surfactant 5 g.

• Let x = fraction of Tween 80: 15.0x + 4.3(1 − x) = 12 → 10.7x = 7.7 → x = 0.7196.
• Tween 80 = 0.7196 × 5 = 3.60 g; Span 80 = 1.40 g.
• Check: (3.60 × 15.0 + 1.40 × 4.3)/5 = (54.0 + 6.02)/5 = 60.02/5 = 12.0. Correct.

Example 4 - displacement value. Prepare 12 suppositories of 1 g mould calibration, each containing 300 mg zinc oxide (DV = 4.7).

• Total drug = 12 × 0.300 = 3.60 g.
• Base displaced = 3.60 / 4.7 = 0.766 g.
• Base required = (12 × 1) − 0.766 = 11.234 g for 12; in practice calculate for 14-15 to allow for mould losses.
• If DV were ignored, 12 g of base plus 3.6 g drug = 15.6 g of mass for a 12 g mould - roughly 3 extra suppositories' worth overflows and each unit is under-dosed.

Example 5 - dry gum primary emulsion. Make 200 mL of a 30% v/v castor oil emulsion with acacia.

• Oil = 60 mL. Dry gum ratio 4:2:1 → water 30 mL, acacia 15 g for the primary emulsion.
• Triturate 60 mL oil with 15 g acacia in a dry mortar, add 30 mL water in one lot, triturate until the characteristic clicking sound and a white creamy primary emulsion forms.
• Dilute gradually to 200 mL with water (plus preservative and flavour); internal phase 30% v/v is well below the inversion limit.

Where it is used

• Oral liquid plants: antacid suspensions (magnesium/aluminium hydroxide), paracetamol and ibuprofen suspensions, albendazole, ORS solutions, iron and multivitamin syrups, dry syrups of amoxicillin and cefixime - Cipla, Sun, Alkem, Mankind, Hetero, Abbott India.
• Topical and dermatology: clotrimazole and ketoconazole creams, diclofenac gels, calamine lotion, zinc oxide paste, silver sulphadiazine cream - Glenmark, Cipla, Galderma India, Ranbaxy-legacy lines.
• Ayurvedic and OTC/cosmetic manufacture: Dabur, Himalaya, Emami, Patanjali - asavas, arishtas, oils, balms, gels, lotions made under the Drugs and Cosmetics Act with ASU licensing and (for cosmetics) the Cosmetics Rules, 2020.
• Job roles: formulation and development scientist (R&D), production officer on liquid orals and ointment blocks, QA/QC analyst running assay, pH, viscosity, sedimentation volume and microbial limit tests, regulatory affairs preparing CDSCO or export dossiers.
• Hospital and community pharmacy: extemporaneous mixtures, reconstitution and dating of dry syrups, counselling on "shake well", suppository insertion and cream application.
• Veterinary and agri-pharma: oral drench suspensions, pour-on emulsions, teat dips - Zoetis India, Virbac, Intas (Pharmaspecialities).

Interview questions

• Q: Why is a flocculated suspension preferred to a deflocculated one? A: Flocs settle quickly but into a loose, high-volume sediment that redisperses in a few shakes; a deflocculated suspension settles slowly yet compacts into a hard cake that cannot be redispersed, making the dose non-uniform.
• Q: Why is simple syrup not preserved? A: At 66.7% w/w sucrose the water activity is too low for microbial growth, so it is self-preserving; dilution of the syrup destroys that protection and then a preservative is required.
• Q: What is HLB and how do you use it practically? A: Hydrophile-lipophile balance is a 0-20 scale of a surfactant's relative affinity for water and oil; you select or blend surfactants to match the required HLB of the oil - roughly 3-6 for w/o and 8-18 for o/w systems.
• Q: Differentiate creaming from cracking. A: Creaming is reversible separation of globules upward or downward with the film intact; cracking is coalescence of globules after film rupture and is irreversible.
• Q: How do you identify whether an emulsion is o/w or w/o? A: Dilute it (it mixes with its external phase), use a water-soluble dye like amaranth (uniform colour means an aqueous external phase) and check conductivity - o/w conducts, w/o does not.
• Q: Why do we need displacement value in suppository manufacture? A: Moulds are calibrated by volume with pure base, but drug occupies volume with a different density; DV tells how much base to subtract so the dose and unit weight are both correct.
• Q: Why does cocoa butter need careful heating? A: It is polymorphic - heating above about 36 °C converts it to unstable low-melting forms that take a long time to solidify, so it is melted gently to just a paste consistency.
• Q: What is thixotropy and why is it desirable? A: A time-dependent fall in viscosity under shear with recovery on standing; the product is a gel in the bottle or tube (suspending and non-running) and pours or spreads when shaken or rubbed.
• Q: Which ointment base would you choose for a weeping eczematous lesion, and why? A: A water-soluble or water-removable base such as PEG ointment or an o/w cream, because it absorbs exudate and washes off; an occlusive hydrocarbon base would trap moisture.
• Q: Why does sodium benzoate fail as a preservative in a syrup at pH 7? A: Only the unionised benzoic acid is antimicrobial; with pKa about 4.2, almost none is unionised at pH 7, so the preservative is effectively inactive.
• Q: Why can a paraben preserved cream still fail a microbial test? A: The paraben can partition into the oil phase or be bound by nonionic surfactants such as polysorbates, leaving the aqueous phase - where microbes grow - under-protected.
• Q: Which tests are specific to ophthalmic ointments? A: Sterility, metal particles test and leakage/fill tests, besides the usual assay and particle-size checks; they are manufactured in a sterile area with sterilised bases.

Common mistakes

• Writing that a deflocculated suspension is more stable because it settles slowly - the caking that follows is the real failure.
• Using the wrong dry-gum ratio: 4:2:1 is for fixed oils, 2:2:1 for volatile oils, 3:2:1 for liquid paraffin; and the gum must be triturated in a dry mortar.
• Omitting displacement value or forgetting the 15-20% excess base when calculating suppository batches.
• Confusing creaming with cracking, or quoting HLB ranges reversed (3-6 is w/o, not o/w).
• Mixing units in Stokes' law - µm with m, cP with Pa·s - giving answers off by 10⁶ or 10³.
• Adding volatile ingredients (menthol, camphor, perfumes) to a hot molten base so they evaporate, instead of near congealing below about 40 °C.
• Incorporating a gritty powder without levigation, then calling the roughness a base defect.
• Calling an elixir a syrup, or labelling a solution "shake well before use" when only biphasic products need it.

Related topics

Dosage forms · Tablets and capsules · Sterile products and parenterals · Novel drug delivery systems · Biopharmaceutics and pharmacokinetics · Physical pharmaceutics: rheology and surface phenomena