Roller compaction is the default dry granulation route for colistin sulphate in immediate-release tablet cores because the API exhibits angle of repose values above 45° and bulk densities in the range 0.18–0.25 g/mL, making direct compression at 10.0% w/w drug load prone to segregation. A 25 mg tablet core formulated to 250 mg total weight contains 10.0% w/w colistin sulphate, microcrystalline cellulose PH102 45.0–55.0% w/w, lactose monohydrate 30.0–40.0% w/w, crospovidone 3.0–5.0% w/w, colloidal silicon dioxide 0.5–1.0% w/w and magnesium stearate 0.5–1.5% w/w. Before processing, the API is dried in a vacuum oven at 40 ± 2°C to a moisture content ≤ 2.0% w/w by Karl Fischer titration (Ph. Eur. 2.5.12) when ambient relative humidity exceeds 60%, because water uptake above 60% RH produces cohesive agglomerates that interfere with ribbon integrity. The preblend is passed through a 500 µm stainless-steel screen and mixed in a tumble blender at 25 rpm for 15 minutes; the colistin sulphate fraction is geometrically diluted with microcrystalline cellulose before addition of lactose to reduce electrostatic adhesion to vessel walls. Roller compaction is operated to obtain ribbon solid fraction between 0.60 and 0.70; this is controlled by roll force, roll speed and gap width rather than by compression force alone. Compacted ribbons are milled through an oscillating screen mill fitted with a 0.8 mm screen; granules outside the 180–1000 µm interval are recycled to the compactor at no more than 25% of fresh feed, because excessive recycle increases work-hardening and reduces compactability. Final compression on a rotary press targeting 10–12 kN force produces tablets with hardness 60–80 N, friability not more than 1.0% w/w per Ph. Eur. 2.9.7 and disintegration time not more than 30 minutes in purified water at 37 ± 2°C per Ph. Eur. 2.9.1. Film coating is applied in a side-vented perforated pan with an aqueous HPMC/PVA system at 3.0–4.0% weight gain; the coat functions as a moisture barrier and not as a release-controlling membrane. Batch release includes potency by Ph. Eur. 2.7.2, uniformity of dosage units by Ph. Eur. 2.9.40 or USP <905> with acceptance value ≤ 15.0, and related substances by HPLC with the method specified in Ph. Eur. 0320. The terminal dosage form is an immediate-release film-coated tablet intended for local action in the gastrointestinal tract; oral bioavailability of colistin sulphate in mammals with intact gut is negligible, which defines the therapeutic rationale for oral solid forms.

What Limits Capsule Fill Weight Uniformity at 12.5 mg Potency?

At 12.5 mg unit potency, the limiting variable is not assay sensitivity but particle-size distribution and triboelectric charge of the colistin sulphate preblend. Hard HPMC capsules size 3 with a target fill weight of 250 mg are preferred over gelatin because HPMC has lower initial moisture and lower oxygen permeability; gelatin capsules can transfer moisture to the hygroscopic API and soften at the fill station. The formulation uses 5.0% w/w colistin sulphate, 75.0–80.0% w/w lactose monohydrate 200 mesh, 10.0–12.0% w/w microcrystalline cellulose PH102, 2.0–4.0% w/w croscarmellose sodium, 0.5–1.0% w/w magnesium stearate and 0.2–0.5% w/w colloidal silicon dioxide. API particle size is controlled to D90 ≤ 150 µm and D50 between 50 µm and 90 µm; finer material below D10 5 µm increases adhesion to machine contact surfaces and produces capillary bridging in high-humidity environments. The blend is prepared by geometric dilution: colistin sulphate is preblended with an equal mass of lactose through a 250 µm screen, then diluted stepwise with lactose and microcrystalline cellulose in a low-shear tumble blender at 25 rpm for 20 minutes. Lubricant is added last and mixed for 3 minutes to limit shear-induced charge. Powder bed height in the capsule filler is maintained below 30 mm and relative humidity at the fill station is kept at 35–45% RH; higher humidity increases the angle of repose above 50° and causes erratic dosator fill weight. A dosing-disc or tamping-pin machine is operated at fill weights of 245–255 mg and capsule closure length is verified every 30 minutes. Weight variation acceptance follows Ph. Eur. 2.9.5 and content uniformity follows Ph. Eur. 2.9.40 or USP <905> with AV ≤ 15.0. Dissolution testing, where a monograph exists, uses USP <711> apparatus 2 at 50 rpm in 900 mL purified water at 37 ± 0.5°C; the Q-value is product-specific and must be validated for the selected capsule shell because HPMC can lag gelatin by 5–10 minutes in disintegration under low-pH conditions. The terminal product is a hard HPMC capsule, optionally banded at the cap-body joint with a 2.5% w/w HPMC solution to reduce moisture ingress and provide tamper evidence.

In top-spray fluid-bed granulation of colistin sulphate for single-dose oral suspension sachets, the binder solution is applied as an aqueous hypromellose E5 solution at 5.0% w/w solids content. The drug substance is pre-dissolved in the citrate-buffered binder solution at pH 5.5 to achieve molecular dispersion; this removes assay variability from granule cores but requires immediate processing because the aqueous API solution undergoes pH-dependent hydrolysis. The granulation batch contains 5.0% w/w colistin sulphate, 65.0–75.0% w/w sorbitol, 2.0–4.0% w/w hypromellose E5, 0.5–1.5% w/w sodium citrate dihydrate, 0.5–1.0% w/w citric acid monohydrate, 0.2–0.5% w/w xanthan gum, 0.2–0.5% w/w colloidal silicon dioxide and 0.1–0.3% w/w flavour. The bed is charged with sorbitol and part of the silicate; the API-buffer-binder solution is sprayed at inlet air temperature 55–65°C, product bed temperature 35–40°C and atomising air pressure 1.2–1.8 bar. Spray rate is adjusted to maintain bed moisture below 15% w/w and is stopped before lumping; granules are dried to loss-on-drying ≤ 2.5% w/w and screened through 1.0 mm. The granule fraction retained on 180 µm should exceed 85% w/w to prevent segregation in the sachet fill line. Single-dose sachets are filled on a form-fill-seal machine with moisture-barrier laminate to 2.5 g ± 5% per Ph. Eur. 2.9.5; content uniformity is verified per Ph. Eur. 2.9.40 or USP <905>. Upon reconstitution with 5 mL purified water, the suspension should disperse within 60 seconds with pH between 5.0 and 6.5 and viscosity 250–500 mPa·s at 25°C to prevent rapid settling of the sorbitol core. The terminal product is a single-dose oral suspension sachet delivering 12.5 mg colistin sulphate per 5 mL; the unabsorbed drug acts locally in the gut. Because sorbitol is hygroscopic, sachets are not exposed to RH above 50% for more than 4 hours during packaging.

Extemporaneously Compounded Oral Suspension pH Preservative and Beyond-Use Dating

Extemporaneously, the central stability variable is pH-controlled hydrolysis when colistin sulphate bulk API is compounded into oral liquid. The API is freely soluble in water, but aqueous solutions buffered above pH 7.0 degrade by peptide hydrolysis; a citrate buffer pH 5.0–6.0 is therefore incorporated into the suspending vehicle. A common vehicle is 0.5% methylcellulose 1500 in purified water, preserved with a paraben system; the measured viscosity at 25°C is between 250 mPa·s and 500 mPa·s to reduce settling without making pouring difficult. Compounding follows USP <795> for nonsterile preparations. The API is levigated with a small portion of vehicle to form a smooth paste, then incorporated quantitatively into the remaining vehicle; the final suspension is packaged in amber polyethylene terephthalate bottles, because colistin sulphate is light-sensitive in dilute solution. Storage is at 2–8°C to minimise hydrolysis. Beyond-use dating is assigned at 14 days under refrigeration for non-preserved aqueous formulations and up to 35 days for preserved formulations in accordance with USP <795> default stability criteria, unless a batch-specific potency assay supports a longer interval. Potency verification for compounded batches uses a stability-indicating HPLC assay rather than the microbiological assay alone, because degradation products may retain some antimicrobial activity while failing the chromatographic specification. The terminal product is an oral suspension of 12.5 mg/5 mL intended for measurable-dose administration to patients with swallowing difficulty; it is not a parenteral product and must not be administered by any route other than oral. Suspension reconstitution from granules and extemporaneous compounding from API are not interchangeable without a demonstrated dissolution bridge or bioequivalence assessment, because particle size and vehicle viscosity alter the exposed surface area and in vivo residence time.

When Colistin Sulphate Is Compounded Into Aseptic Parenteral Solutions

In aseptic parenteral manufacturing, colistin sulphate is not the human injectable drug of choice; the form authorised in human medicine is colistimethate sodium, a methanesulfonate prodrug that differs in molecular mass, potency label and nephrotoxicity profile. Published data for injectable colistin sulphate in human use are limited, and the two substances cannot be exchanged on an IU-to-IU basis without product-specific conversion. Where colistin sulphate is compounded into a sterile solution for veterinary injectable use, the manufacturing route is aseptic filtration rather than terminal steam sterilisation, because the cyclic peptide hydrolyses under autoclave conditions and loses potency. The solution is prepared by dissolving colistin sulphate in water for injection at a concentration equivalent to 100,000 IU/mL, adjusted to pH 6.0–7.0 with 0.1 N sodium hydroxide or hydrochloric acid. Tonicity is adjusted with sodium chloride to 290 ± 10 mOsmol/kg; hypotonic formulations cause injection-site pain and haemolysis in target species. After dissolution, the solution is prefiltered through a 0.45 µm membrane and sterilised through a 0.22 µm PVDF or PES low-protein-binding membrane; nylon filters are avoided because of peptide adsorption. The filtrate is filled into Type I borosilicate glass vials or polyethylene ampoules under Grade A conditions, with fill volume overage not exceeding 1.5% and sterility assurance based on environmental monitoring and filter integrity testing per GMP Annex 1. The terminal product is a clear, colourless to pale yellow veterinary injectable solution with pH 6.0–7.0 and osmolality near physiological range. Storage at 2–8°C is required unless experimental stability data show no loss at 25°C; the product must be protected from light. The API lot used in parenteral manufacture must meet bacterial endotoxin limits by Ph. Eur. 2.6.14 or USP <85>; for parenteral products the limit is derived from maximum bolus dose and is stated in the marketing authorisation. Sterility of the finished product is confirmed by Ph. Eur. 2.6.1 or USP <71>; particulate matter is controlled by Ph. Eur. 2.9.19 or USP <788>. The formulation must not be combined with divalent cation-containing diluents or other peptide antibiotics in the same infusion line without documented compatibility, because physical precipitation cannot be excluded at high peptide concentrations.