The product designated Amlodipine Besilate Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable is the benzenesulfonate salt of amlodipine, a dihydropyridine calcium-channel antagonist. The active substance is described by the systematic name 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methylpyridine-3,5-dicarboxylic acid 3-ethyl 5-methyl ester benzenesulfonate, CAS 111470-99-6, molecular formula C₂₀H₂₅ClN₂O₅·C₆H₆O₃S, and relative molecular mass 567.05 g/mol. Ph. Eur. uses the spelling “besilate”; USP and JP use “besylate.” The designation “Pharma Grade API” indicates manufacture under ICH Q7 GMP, with an active substance master file/ASMF and batch release against a pharmacopoeial monograph and a registered specification. The reference to tablet, capsule, granule, injection, oral, and injectable routes is not a single universal specification; it defines a route-compatible grade strategy in which solid-oral and parenteral presentations share the same salt but differ in control of particle size, bioburden, endotoxin, residual solvent, and elemental impurity risk.

Dose equivalence is a defining characteristic. The relative molecular mass ratio of the besilate salt to amlodipine base is 567.05/408.88 ≈ 1.387. Consequently, 5 mg of amlodipine base corresponds to 6.94 mg of amlodipine besilate, and 10 mg of base corresponds to 13.87 mg of besilate. Batch calculations for tablet and capsule formulations must use this factor unless the label expresses strength as amlodipine besilate; most pharmacopoeial monographs and regulatory dossiers express strength as amlodipine base. Substitution of a different salt without adjustment changes the molar amount of active moiety and requires revalidation of assay, content uniformity, dissolution, and bioequivalence.

What Distinguishes Amlodipine Besilate from Other Amlodipine Salts?

Amlodipine is a weak base; the free base has poor aqueous solubility, while the besilate salt is a pharmacopoeially established solid form with improved dissolution in the acidic-to-neutral pH range relevant to oral absorption. The counterion is benzenesulfonic acid, which is non-volatile, strongly acidic, and contributes 158.18 g/mol to the salt. The salt form is selected for stable crystalline packing, processability, and acceptable chemical stability under normal storage conditions. Alternative salts such as mesilate, maleate, and hydrobromide are not automatically interchangeable; they differ in counterion mass, hygroscopicity, pH of saturated solution, and degradation products. In a pharmaceutical development context, a change from besilate to another salt triggers ICH Q3A impurity qualification and ICH Q6A specification justification, as well as a fresh bioequivalence study unless a biowaiver is justified under the applicable regional guidance.

The clinically used amlodipine besilate is the racemic mixture of the S and R enantiomers. Levamlodipine besilate is the S-enantiomer-specific product. The two materials are not identical: levamlodipine has different pharmacological activity, a separate monograph, and a different dose equivalence. Products labelled “amlodipine besilate” should not be substituted with “levamlodipine besilate” in master formula records. Where chiral identity is a release criterion, it is typically controlled by chiral HPLC or optical rotation; the Ph. Eur. monograph for amlodipine besilate does not include a chiral purity limit because the racemate is the defined active substance.

The main difference between this product and non-pharmaceutical amlodipine salt variants is the absence of a pharmacopoeial monograph, a DMF/ASMF, and GMP release for the latter. Food or research-grade material should not be used in a licensed dosage form because residual solvent, impurity, and microbiological profiles are not controlled under ICH Q7. The phrase “Pharma Grade API” should be evidenced by a certificate of analysis issued against a registered specification, a batch manufacturing record review, and a supplier audit report; commercial purchase without such documentation does not meet EU GMP Part II or 21 CFR 211.84 incoming component requirements.

Compendial release limits and ICH Q3A thresholds

Pharmacopoeial monographs for amlodipine besilate specify identification by infrared spectrophotometry and HPLC retention time, assay by liquid chromatography, related substances by liquid chromatography, and loss on drying/water. A typical compendial alignment uses assay 98.0–101.0% on the dried basis and total impurities controlled by ICH Q3A thresholds. The thresholds below apply to a maximum daily dose of 10 mg amlodipine; lower-dose products can use the same thresholds because the daily dose remains within the ≤ 2 g/day ICH Q3A band.

Residual solvents are controlled under ICH Q3C. If the synthesis uses methanol, dichloromethane, tetrahydrofuran, or N,N-dimethylformamide, the corresponding concentration limits are 3000 ppm, 600 ppm, 720 ppm, and 880 ppm, respectively. Class 1 solvents such as benzene are limited to 2 ppm. Elemental impurities are assessed under ICH Q3D; the parenteral route requires a more conservative permitted daily exposure profile than the oral route for Class 1 elements such as lead, cadmium, arsenic, and mercury. The analytical methods are typically ICP-MS or ICP-OES for elemental impurities and headspace gas chromatography for residual solvents.

Water content is determined by Ph. Eur. 2.5.12 or USP <921>; the acceptance criterion is established from stability data, with parenteral grades usually controlled at a lower moisture limit than direct compression grades. Infrared identification follows Ph. Eur. 2.2.24 or USP <197K>, and the HPLC assay follows Ph. Eur. 2.2.29 or USP <621>. Particle-size distribution for solid-oral grades is measured by laser diffraction according to Ph. Eur. 2.9.31, USP <429>, and ISO 13320.

When the Same Benzenesulfonate Salt Is Supplied for Injectable Formulations

Injectable presentation changes the critical quality attribute hierarchy. Microbial quality is no longer a low-risk oral concern; the active substance must be supplied with a low bioburden and a validated endotoxin profile. The drug product manufacturer typically performs sterile filtration of the final solution under aseptic conditions; if the API contributes particles that challenge the filter, the grade can be controlled by particle size reduction and clarified at the manufacturing site. Bacterial endotoxin limits for the finished injection are set by Ph. Eur. 2.6.14/USP <85> based on the maximum bolus dose and route. For the active substance, an endotoxin limit is usually derived from the maximum concentration in the formulation and the dose volume; published data for this specific configuration is limited, so the limit is product-specific and must be justified in the marketing authorisation dossier.

Parenteral formulations also require stricter control of elemental impurities because the permitted daily exposure values in ICH Q3D are lower for parenteral administration. The synthesis and packaging train must avoid stainless-steel contact unless passivation is demonstrated, and the API should be packed in aluminium laminate bags with low particulate shedding. Residual solvent selection for an injectable grade should favour solvents with high no-observed-adverse-effect levels and high volatility; if a Class 2 solvent is unavoidable, its limit must comply with ICH Q3C but is often tightened from the oral limit based on route, dose volume, and patient population. No universal relaxation of assay or impurity limits is acceptable for injectable use.

Finished parenteral products must additionally meet sterility according to Ph. Eur. 2.6.1/USP <71> and sub-visible particulate matter according to Ph. Eur. 2.9.19/USP <788>. These tests belong to the finished product specification, not the API release specification, but the API grade must not introduce microbiological or particle burdens that cannot be removed by qualified filtration. Aseptic processing is usually preferred for amlodipine besilate injection because the dihydropyridine ring can degrade under excessive thermal stress; terminal sterilisation may be acceptable only if forced degradation data demonstrate chemical stability at the selected sterilisation time-temperature profile.

Solid-state form and particle engineering determine process capability

Amlodipine besilate can exist in multiple crystalline forms. The selected form should be controlled by X-ray powder diffraction, and the amorphic or partially amorphous fraction should be monitored when milling is used. A change in polymorphic composition can alter dissolution rate, excipient compatibility, and compressibility. For direct compression and capsule filling, particle size is not a universal parameter; it must be established through blend uniformity studies. Highly cohesive powders with a Carr index above 35 generally require glidant addition or granulation, but published data for this specific configuration is limited and the final flow requirement depends on the chosen tablet press or capsule filler model.

Milling for solid-oral grades may be performed in a pin mill or fluid-energy mill. The milling step should be controlled by feed rate, gas pressure, and classifier speed; over-milling generates electrostatic charge and poor flow, while under-milling may leave agglomerates that segregate during transfer. For low-dose tablet formulations, the API is typically blended with microcrystalline cellulose, calcium hydrogen phosphate dihydrate, sodium starch glycolate, and magnesium stearate. The magnesium stearate level is commonly 0.25–1.0% w/w; prolonged lubrication can delay dissolution by forming a hydrophobic film on the API surface.

Wet granulation with pregelatinised starch or microcrystalline cellulose requires a drying endpoint established by stability data. A common starting point for fluid-bed drying is inlet air at 50–60°C, but it is not a substitution for forced degradation data. The API is light-sensitive, and wet mass should be protected from extended exposure to ultraviolet or daylight. Dry granulation by roller compaction can avoid moisture but introduces particle-size enlargement and requires re-milling and lubrication optimization. Tablet compression should be designed using a compaction simulator or small-scale rotary press; compression force, precompression, and dwell time are product-specific and cannot be transferred from a different amlodipine formulation without a validated compression profile.

Granule presentations intended for sachets or reconstitution should specify sieve fractions and bulk density because these parameters influence filling volume and reconstitution time. Bulk density and tapped density follow Ph. Eur. 2.9.34/USP <616>; powder flow may be assessed according to USP <1174>. Capsule filling on dosator or tamping machines requires a powder with sufficient flow and low adhesion to steel and gelatin/HPMC surfaces. Dissolution testing should be carried out per Ph. Eur. 2.9.3/USP <711> using a validated medium; amlodipine besilate is soluble enough that routine quality control can use aqueous buffer at pH 6.8 or simulated gastric fluid, but the discriminating power of the medium must be established during method development.

Stability of amlodipine besilate is adequate under controlled room temperature; however, the API should be stored in tight, light-resistant containers. Long-term storage conditions are usually 25°C ± 2°C at 60% RH ± 5% RH for climatic zone II, with accelerated testing at 40°C ± 2°C and 75% RH ± 5% RH according to ICH Q1A. Dry heat and prolonged light exposure should be avoided. Shipping under cold chain is not normally required for amlodipine besilate; however, the parenteral grade should be protected from humidity excursions above 65% RH unless container closure integrity is validated.