| HS Code | 282566 |
| Product Name | Calcium Butyrate Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable |
| Synonyms | Calcium Butanoate; Butanoic Acid Calcium Salt; Calcium Butyrate |
| Chemical Formula | C8H14CaO4 |
| Molecular Weight | 214.27 g/mol |
| Cas Number | 5743-36-2 |
| Appearance | White to off-white crystalline powder |
| Odor | Slight butyric odor |
| Assay | 98.0% to 102.0% on dried basis |
| Grade | Pharma Grade / API Grade |
| Solubility | Soluble in water; slightly soluble in ethanol |
| Ph | 7.0 to 9.0 for 5% aqueous solution |
| Sterility | Sterile for injectable grade |
| Storage | Store in a cool, dry, well-ventilated place protected from moisture and light |
| Shelf Life | 24 to 36 months in unopened original packaging |
| Packaging | 25 kg fiber drum with double polyethylene liner; customized packaging available |
| Dosage Forms | Tablet, Capsule, Granule, Injection |
| Routes Of Administration | Oral, Injectable |
| Pharmacopoeia Standard | In-house specification; complies with ICH Q3C residual solvents |
As an accredited Calcium Butyrate Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
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Direct compression of calcium butyrate pharma grade in a colonic-release matrix imposes a narrow processing window because the salt is freely soluble in aqueous media. In an unprotected matrix, a 10.0 mm round core releases more than 80% of the labelled butyrate into 0.1 N HCl within 60 min under USP <711> Apparatus II at 50 rpm; this failure mode is detected at the first dissolution assessment after compression. A representative formulation contains 55–70 wt% calcium butyrate, 15–25 wt% hypromellose K100M, 5–10 wt% ethylcellulose 10 cP, 3–5 wt% citric acid monohydrate, 0.5–1.0 wt% magnesium stearate, and 0.5–1.5 wt% colloidal silicon dioxide. The citric acid fraction is not a fixed additive; it is adjusted against the micro-pH of a wetted tablet surface so that the coating polymer does not hydrate prematurely. If the surface pH exceeds 5.5 during dissolution, Eudragit FS 30 D or L 30 D-55 may partially dissolve before the target zone, and if the surface pH falls below 3.5, free butyric acid volatilization increases and the tablet develops a rancid headspace odor. Compression is performed on a 16-station rotary tablet press with 10.0 mm round flat-faced bevel-edge tooling; turret speed is held at 25–40 rpm, precompression force at 3–5 kN, and main compression force at 8–15 kN. Tablet hardness is maintained at 60–120 N by USP <1217>, and friability is controlled below 0.8% by USP <1216>. The core is coated in a side-vented pan at inlet air 50–60°C, product temperature 28–35°C, and spray rate 8–15 g/min/kg; coating weight gain is fixed at 10–15% for colon-targeted release. If the bulk density of the API batch is below 0.45 g/mL, direct compression becomes non-robust and die fill weight varies beyond ±5%; the batch is dry-granulated by roller compaction at ribbon density 1.10–1.30 g/cm³ before compression. In phosphate-based dissolution media, soluble calcium may produce turbidity that interferes with UV detection; the validated release method therefore includes a 0.45 µm PVDF syringe filter and ion-exclusion HPLC with an organic acid column rather than direct UV detection.
| Test | Method | Acceptance limit |
|---|---|---|
| Release, acid stage | USP <711>, 0.1 N HCl, 2 h | ≤10% labelled butyrate released |
| Release, buffer stage | USP <711>, pH 6.8 acetate/borate, 8 h | ≥80% released within 8 h |
| Uniformity of dosage units | USP <905> | acceptance value ≤15 |
| Friability | USP <1216> | ≤0.8% |
| Water content | Karl Fischer, USP <921> | ≤2.0% |
In capsule filling operations, calcium butyrate is not processed as a direct powder blend when the label claim exceeds 200 mg because the API and dense fillers segregate under hopper vibration and the fill weight variation exceeds the acceptance value of USP <905>. The standard platform is extruded-spheronized pellets. Wet mass contains 40–55 wt% calcium butyrate, 30–45 wt% microcrystalline cellulose Avicel PH-101, 5–10 wt% lactose monohydrate, and purified water at 28–35 wt% of dry mass. Over-wetting is the main batch failure; above 35 wt% water, the mass coats the spheronizer plate and the yield above 1250 µm exceeds 20%. Extrusion is performed through a 0.8–1.0 mm screen at screw speed 25–45 rpm, followed by spheronization at 700–1200 rpm for 3–6 min. The accepted pellet fraction is 800–1250 µm, with ≥85% yield and mean aspect ratio ≤1.2; pellets outside this range are rejected because they alter dosator plug height and fill weight. Drying in a fluid-bed dryer with inlet air 50–60°C and product temperature 35–42°C continues until moisture is <1.5% by USP <921>. Dried pellets are coated with an aqueous ethylcellulose dispersion such as Surelease E-7-19040 to 10–15% weight gain, cured at 60°C for 2 h, and blended with 0.3–0.5% talc before encapsulation. On a tamping-pin capsule machine, pellet bulk density must be 0.65–0.85 g/mL, tapped density 0.75–0.95 g/mL, angle of repose ≤35°, and fines below 250 µm must be <10%; otherwise the fill weight range for a size 0 capsule exceeds ±7.5% and the batch fails USP <905>. The extruder screw load is recorded; a load rise of more than 20% from the batch mean indicates over-wetting or binder accumulation and triggers an immediate feed stop. The final capsule is intended for distal intestinal release where local short-chain fatty acid exposure is desired.
When a dosage form must be dispersed before oral administration, granule-based sachets provide dose titration and avoid the swallowing burden of intact tablets. The manufacturing route is fluid-bed top-spray granulation; high-shear mixing is not used for calcium butyrate because the impeller compacts fines into dense agglomerates that wet poorly and sediment rapidly. Povidone K30 at 5% w/w in ethanol/water 70:30 v/v is sprayed onto a pre-blend of calcium butyrate, mannitol, and maltodextrin in a Glatt GPCG 1.1 at inlet air 45–55°C, product temperature 30–38°C, and spray rate 20–30 g/min. In a 2 kg batch, spray time is approximately 45–60 min; if the exhaust humidity exceeds 60% RH, the granule agglomerates and the yield below 250 µm can increase above 15%. The granule target is 250–800 µm with ≥80% of the mass between 315 µm and 630 µm; particles above 800 µm settle before the dose is transferred, and particles below 250 µm generate odor-laden dust. Residual ethanol is controlled by headspace GC below 5000 ppm under ICH Q3C Option 2. The final sachet contains 500 mg calcium butyrate, equivalent to 406.5 mg butyrate anion on an anhydrous basis, using the theoretical butyrate anion content of 81.3% w/w. The laminate is polyethylene/aluminium/polyethylene; seal strength is >35 N/15 mm per ASTM F88/F88M-21 and oxygen transmission rate is <0.5 cm³/m²·24 h·atm per ASTM D3985 at 23°C and 0% RH. Before administration, the granule is dispersed in 20–50 mL water; the dispersion remains homogeneous for 30 min if the granule wetting time is <60 s and the settled fraction after 60 s is <10%. Butyric acid odor is controlled at the source by maintaining the granulator exhaust under negative pressure -20 to -50 Pa and by wet scrubbing before discharge.
For parenteral development, calcium butyrate is characterized without a dedicated USP or Ph. Eur. injectable monograph; the drug substance specification is assembled from ICH Q6A universal tests, ICH Q3D elemental impurity limits, and aseptic processing requirements of 21 CFR 211.110 for in-process sampling. The powder for sterile filtration or lyophilization is controlled with particle size d50 ≤10 µm, d90 ≤25 µm, water content <1.0%, and bacterial endotoxins <0.5 EU/mg by kinetic chromogenic LAL, USP <85>, Ph. Eur. 2.6.14. Aseptic dissolution is performed at 50 mg/mL in Water for Injection at 20–25°C; complete dissolution is required before filtration because residual particles above 0.22 µm foul the sterilising membrane and reduce throughput. The solution is passed through a 0.45 µm polyethersulfone prefilter and a 0.22 µm PVDF sterilising filter; differential pressure is held below 1.5 bar to prevent filter rupture, and the filtrate is filled in 5 mL aliquots into Type I borosilicate vials. Vial fill weight is check-weighed every 15 min; any fill outside ±3% triggers an automatic no-fill interlock on the aseptic filling line. Lyophilization uses a shelf ramp from -40°C to -20°C over 4 h, primary drying at -15°C and 0.2 mbar for 20–30 h, and secondary drying at 35°C for 6 h. The lyophilised cake is tested for appearance, reconstitution time, assay, related substances, moisture <2.0% by USP <921>, container closure integrity by USP <1207>, subvisible particles by USP <788>, sterility by USP <71>, and bacterial endotoxins by USP <85>. Terminal moist-heat sterilization at 121°C is not used because the heat load can volatilize free butyric acid, produce a pH drop, and destabilize the stoichiometric salt. The following compendial matrix applies to each manufactured lot.
| Attribute | Method/standard | Limit |
|---|---|---|
| Bacterial endotoxin | USP <85>, Ph. Eur. 2.6.14 | <0.5 EU/mg |
| Subvisible particles ≥10 µm | USP <788> light obscuration | ≤6000 per container |
| Subvisible particles ≥25 µm | USP <788> light obscuration | ≤600 per container |
| Sterility | USP <71> | sterile |
| Water content | USP <921> | <2.0% |
| Container closure integrity | USP <1207> | no leak |
Reconstitution and dilution of lyophilised calcium butyrate cannot proceed without a documented absence of phosphate in the infusion vehicle. When the calcium cation contacts phosphate-containing diluents, low-solubility calcium phosphate species form as visible haze or subvisible particles; this incompatibility can shift the particulate matter profile beyond USP <788> limits and may obstruct the sterilising membrane in an in-line filter. Because published precipitation data for calcium butyrate in commercial infusion media are limited, a site-specific admixture challenge is performed at the intended clinical concentration using phosphate levels of 0 mM, 1 mM, 5 mM, and 10 mM. Turbidity is quantified by ISO 7027 as nephelometric turbidity units, and the admixture is assayed for butyrate content and pH at 0 h, 4 h, and 24 h. Reconstitution with 10 mL Water for Injection should yield a clear solution within 60 s; if the solution remains hazy after 120 s or contains visible flocs, the vial is rejected. The diluted infusion is prepared in glucose 5% or sodium chloride 0.9% only after confirming the vehicle is phosphate-free and calcium-free and after verifying the final concentration remains below the saturation boundary of the calcium–vehicle system. Administration sets are flushed with glucose 5% before and after infusion to displace residual phosphate from prior infusions. An in-line filter after the Y-site is a 1.2 µm low-protein-binding membrane; if the filter pressure exceeds 0.5 bar above baseline, the infusion is stopped and the admixture is sampled for particle counting. Citrate-containing buffers are not automatically acceptable; citrate chelates free calcium at concentrations above 10 mM, altering the ionization state of butyrate and interfering with the assay unless the method is validated in the presence of the chelator.
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Calcium Butyrate Pharma Grade API is the divalent calcium salt of n-butyric acid, supplied as a white to off-white crystalline powder with a formula weight of 214.28 g/mol for the anhydrous form. The molecule provides 2 mol of butyrate per 1 mol of calcium, whereas sodium butyrate provides 1 mol of butyrate per 1 mol of sodium. Pharmaceutical use is further defined by the finished dosage form: oral tablet, oral capsule, granule for suspension or sachet, and injectable solution require different particle-size, microbial, endotoxin, and hydration specifications. Model selection is therefore based on hydration state and intended route rather than a single universal code. An anhydrous or low-moisture grade is assigned to moisture-sensitive dry processing, a monohydrate or intermediate model may be used for aqueous granulation, and a low-endotoxin micronized model is required for injectable manufacture. The free acid precursor, n-butyric acid, is a liquid with a boiling point of 163.5 °C at 101.3 kPa; the calcium salt is a solid at ambient pressure, which reduces volatile headspace loss and simplifies containment during weighing and blending. The butyrate anion has a pKa of 4.82; below approximately pH 3.0, the protonated free acid becomes the dominant dissolved species in unbuffered aqueous media. This pH-dependent speciation must be controlled in dissolution testing and injectable buffer selection. A feed-grade calcium butyrate is not automatically interchangeable with the pharma grade because raw material controls under 21 CFR 211.84, elemental impurities under ICH Q3D, residual solvent testing under USP <467>, and microbial limits under USP <61> and USP <62> are not guaranteed for nonpharmaceutical material.
A dedicated harmonized monograph for calcium butyrate is not available in all major pharmacopoeias; therefore, the release specification usually combines dossier-defined limits with the general chapters shown in Table 1. Identity of the calcium cation is confirmed quantitatively by complexometric titration or inductively coupled plasma atomic emission spectroscopy; butyrate is confirmed by gas chromatography with flame ionization detection or liquid chromatography with ultraviolet detection against a certified reference standard. Assay on the anhydrous basis is typically 98.0%–102.0% when calculated as Ca(C4H7O2)2. Loss on drying is model-dependent: the anhydrous grade is controlled to 1.0% or less, whereas hydrated models are controlled against an approved water content range. Elemental impurities are controlled using ICH Q3D and measured by USP <233>; limits are not fixed values because the permitted daily exposure for lead, cadmium, arsenic, and mercury must be converted to concentration limits using the maximum daily dose and route of administration. Residual solvents should follow USP <467> or Ph. Eur. 5.4; if ethanol or isopropanol is used in purification, Option 1 limits for Class 3 solvents apply, with total unspecified Class 3 solvents not exceeding 0.5% w/w. For nonsterile oral-grade API, microbial enumeration and specified pathogen testing follow USP <61> and USP <62>; a typical nonsterile oral limit is total aerobic microbial count 10³ CFU/g or less and total yeasts and molds 10² CFU/g or less, with Escherichia coli absent. Injectable-grade API additionally requires a bacterial endotoxin specification derived from USP <85>; the limit is the intravenous K value of 5 EU/kg/h divided by the maximum intended dose in mg/kg/h. Sterility testing per USP <71> applies only when the API is claimed as sterile or is intended for terminal sterilization without further decontamination.
| Parameter | Method or standard | Acceptance criterion |
|---|---|---|
| Appearance | Visual inspection | White to off-white crystalline powder |
| Identity, calcium | USP <191> / Ph. Eur. 2.3.1 | Positive for calcium |
| Identity, butyrate | GC-FID or HPLC-UV retention match | Matches reference standard |
| Assay, anhydrous basis | HPLC-UV or GC after derivatization | 98.0%–102.0% |
| Loss on drying | Ph. Eur. 2.2.32 | Anhydrous: ≤1.0%; hydrated: per approved dossier |
| Elemental impurities | ICH Q3D / USP <233> | Based on PDE for oral or injectable route |
| Residual solvents | USP <467> / Ph. Eur. 5.4 | Option 1 limits; Class 3 total ≤0.5% w/w |
| Microbial enumeration | USP <61> / USP <62> | TAMC ≤10³ CFU/g; TYMC ≤10² CFU/g; E. coli absent |
| Bacterial endotoxins | USP <85> | K/M route-derived limit; injectable grade controlled low |
| Sterility | USP <71> | No growth for sterile injectable-grade claim |
| Particulate matter | USP <788> | Meets volume-specific light obscuration limits after reconstitution |
| Particle size distribution | Ph. Eur. 2.9.31 / ISO 9276-1 | D10, D50, and D90 controlled per finished dosage form |
During solid oral development, the API lot is first characterized by USP <1174> powder flow and Ph. Eur. 2.9.36 flowability. A Carr index above 25 is classified as passable-to-poor flowing and generally requires a force feeder on a rotary tablet press. Particle size distribution is controlled by laser diffraction according to Ph. Eur. 2.9.31 or ISO 9276-1; broad distributions with excessive fine particles below 75 µm increase the risk of segregation, weight variation, and punch sticking. If the active load exceeds 60% w/w in a direct compression tablet, the formulation may be limited by the compactibility of the crystalline salt. A preformulation compaction study on an instrumented rotary press fitted with 8 mm to 10 mm tooling is used to generate force–hardness and ejection force data. When tablet hardness is insufficient, dry granulation by roller compaction is a common alternative; the ribbon density should be measured and controlled because low-density ribbons produce granules with higher friability and excessive fines below 75 µm, leading to capping and variable content uniformity. Content uniformity for low-dose tablets should be assessed by USP <905>. Disintegration is evaluated by USP <701>, and dissolution by USP <711> using apparatus II with pH 4.5 acetate or pH 6.8 phosphate media; pH 1.2 media may generate free butyric acid, which can complicate quantification and is not recommended for routine control without method justification.
Capsule filling of calcium butyrate granules on a tamping-pin machine may require higher bulk density than filling on a vibratory feed unit. Bulk density and tapped density are measured by USP <616>; when the Hausner ratio exceeds 1.25, flow is often classified as passable and the formulation may require glidant or granulation. Anhydrous calcium butyrate should be protected from humid air because moisture uptake can alter the hydration state. Dynamic vapor sorption at 25 °C and 60% RH supplies a moisture-sorption profile that informs handling and packaging. If a hydrated model is used, the certificate of analysis should state the water content range and the assay should be reported on an anhydrous basis.
Wet granulation of the anhydrous model requires careful selection of the granulating fluid because water addition can produce a hydrated form and increase the risk of localized overgranulation. Aqueous binder systems are generally more appropriate for the hydrated model; nonaqueous or hydroalcoholic binder systems are preferred for the anhydrous model in order to preserve the defined hydration state. If an aqueous granulation is unavoidable, the water activity of the dried granule should be monitored and controlled to 0.60 or less at 25 °C if microbial stability or hydration-state drift is a concern. A fluid-bed granulator fitted with a top-spray nozzle is commonly used for this type of material because it allows simultaneous control of inlet air temperature, product temperature, and spray rate. Inlet air temperature must be balanced against the risk of releasing free butyric acid; if the bed temperature is too high, odor and loss of active can increase, while too low a product temperature may permit overwetting. The spray rate should be selected so that the product temperature remains above the dew point of the drying air and below the temperature at which the granule surface becomes sticky. Granule size distribution is measured by sieve analysis per Ph. Eur. 2.9.12 or USP <786>; a typical target is a D50 between 125 µm and 250 µm for capsule filling, but the final limit must be tied to content uniformity and dissolution. Magnesium stearate or sodium stearyl fumarate is added in a low-shear blender; if magnesium stearate is used, total lubricant concentration is usually 0.5% to 1.5% w/w, with mixing time limited to avoid over-lubrication and delayed dissolution. The finished granule is compressed into tablets or filled into hard gelatin or hypromellose capsules. Capsule content uniformity is sensitive to granule particle size, bulk density, and flow; high-speed filling machines with tamping pins may require granules with a Hausner ratio below 1.35. Continuous twin-screw wet granulation with an L/D ratio of 25:1 to 40:1 may be evaluated as an alternative for high-volume production; published data for calcium butyrate in this configuration is limited.
When formulators compare calcium butyrate with sodium butyrate, magnesium butyrate, or free n-butyric acid, stoichiometry and handling behavior are the primary differentiators. Table 2 summarizes the relevant values. On a mass basis, calcium butyrate anhydrous provides 0.00933 mol of butyrate per 1 g; sodium butyrate provides 0.00908 mol per 1 g; and n-butyric acid provides 0.01135 mol per 1 g. The free acid has the highest butyrate equivalent per gram, but it is a liquid with a boiling point of 163.5 °C, a pungent odor, and a tendency to volatilize from open processes. Calcium butyrate and sodium butyrate are solids; the calcium salt introduces one calcium cation per two butyrate anions, while sodium butyrate introduces two sodium cations per two butyrate anions. The choice of cation affects electrolyte load and compatibility. Published comparative moisture-uptake data for the sodium and calcium salts are limited; therefore, lot-specific dynamic vapor sorption at 25 °C and 60% RH is recommended before selecting packaging. For injectable products, calcium-containing solutions must avoid phosphate and carbonate buffers because of precipitation, whereas sodium butyrate does not carry the same divalent-cation precipitation risk. Magnesium butyrate is a divalent alternative, but pharmacopoeial analytical methods and pharmaceutical-grade supply are less commonly reported.
| Property | Calcium butyrate, anhydrous | Sodium butyrate | n-Butyric acid |
|---|---|---|---|
| Chemical form | Divalent salt, solid | Monovalent salt, solid | Free acid, liquid |
| Formula weight | 214.28 g/mol | 110.09 g/mol | 88.11 g/mol |
| Butyrate equivalents per gram | 0.00933 mol/g | 0.00908 mol/g | 0.01135 mol/g |
| Cation load per two butyrate units | 1 calcium ion | 2 sodium ions | None |
| Boiling point or volatility | Solid, low volatility | Solid, low volatility | Liquid, 163.5 °C at 101.3 kPa |
| Principal formulation constraint | Calcium phosphate or carbonate precipitation | Sodium load; reported hygroscopic tendency | Odor, volatility, and free acid handling |
Injectable calcium butyrate formulations require a low-endotoxin micronized or sterile API model. The endotoxin limit is not a fixed value but is calculated from USP <85> as K/M. For an intravenous product, the K value is 5 EU/kg/h; for a 70 kg adult, this corresponds to a maximum permitted endotoxin exposure of 350 EU/h divided by the maximum dose per hour. If the maximum dose is 1 g/h, the calculated limit is 0.35 EU/mg; if the maximum dose is 500 mg/h, the calculated limit is 0.70 EU/mg. The API must also meet particulate matter limits after reconstitution per USP <788>. For large-volume injectable solutions, light obscuration particle counts are typically 25 particles/mL or less at ≥10 µm and 3 particles/mL or less at ≥25 µm. Buffer selection is constrained by the divalent calcium cation: phosphate-buffered saline and carbonate-based buffers are poor choices because calcium phosphate and calcium carbonate precipitates may form at neutral to slightly alkaline pH. Citrate can chelate calcium and alter the free calcium concentration; therefore, compatibility studies should include visual inspection, pH, and light obscuration particulate counts at 0 h, 24 h, and 48 h. If terminal sterilization by autoclave is desired, the solution stability of calcium butyrate at 121 °C for 15 min must be confirmed by assay and degradation product profiling. Sterile filtration through a 0.22 µm membrane is an alternative for heat-sensitive formulations, but it requires a prefilter and validation of bacterial retention under production conditions. Because the free acid pKa is 4.82, injectable solutions should be pH-controlled; at low pH the equilibrium species shifts to protonated butyric acid, which may be lost through the headspace or partition into plastic containers. The injectable grade should be manufactured in accordance with 21 CFR 210 and 21 CFR 211, and the API should be tested for bioburden prior to sterile processing. Sterility is a separate claim governed by USP <71>; a low-endotoxin micronized API is not automatically sterile unless it is sterilized and released as such.
