Hydroxyethyl Starch 130/0.4 Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable is a hydroxyethylated waxy maize starch derivative in which weight-average molecular weight is controlled to approximately 130 000 Da and molar substitution is controlled to 0.40–0.45. The designation 130/0.4 encodes the two release-critical variables that determine amylase degradation rate, renal clearance, and colloid osmotic pressure: the first element is the approximate weight-average molecular weight in kilodaltons, and the second is the molar substitution expressed as moles of hydroxyethyl groups per anhydroglucose unit. The material is produced by alkaline hydroxyethylation of waxy maize starch followed by controlled acid hydrolysis, neutralization, purification, precipitation, and spray drying or milling. Unlike native starch or pregelatinized starch, the hydroxyethyl groups disrupt interchain hydrogen bonding and permit cold-water swelling. This property allows the polymer to be evaluated as a binder, filler, or matrix former in oral solid dosage forms and as a plasma volume expansion agent after dissolution in isotonic saline. Published data for oral therapeutic applications of this specific hydroxyethyl starch grade remain limited, while injectable use is documented in hypovolemia management.

Pharmacopoeial Identity and Critical Quality Attributes of the 130/0.4 Grade

Release of the material for pharmaceutical use is governed by specifications aligned with current compendial and International Council for Harmonisation expectations. The dry powder presents as a white to off-white, free-flowing powder for spray-dried lots and as a finer, more cohesive powder for milled lots. Identification is confirmed by infrared absorption spectrophotometry against a reference spectrum and by a starch color test; a positive blue-violet complex with iodine differentiates the starch backbone from synthetic polymers.

The molecular weight distribution is measured by size-exclusion chromatography with multi-angle laser light scattering or refractive index detection. A pharma-grade lot is specified with Mw between 110 000 Da and 150 000 Da, and the polydispersity index is typically controlled below 2.0 because low-molecular-weight fractions below the renal threshold shorten the effective plasma half-life, while high-molecular-weight fractions increase tissue retention. Molar substitution is controlled between 0.38 and 0.45, and the C2/C6 hydroxyethyl substitution ratio is maintained above 7:1; a higher ratio on C2 reduces accessibility of the glycosidic bond to alpha-amylase and extends the residence time of the polymer. Elemental impurities are controlled under ICH Q3D, residual solvents under ICH Q3C, and microbial quality under the intended route of administration.

Because the hydroxyethyl substitution reduces gelatinization temperature and permits hydration below 40 °C, aqueous binder preparation does not require boiling, unlike native corn starch. For tablet wet granulation, a 5% w/w aqueous dispersion is hydrated at 50–60 °C for 20–30 min to form a low-viscosity, shear-thinning binder solution; viscosity at 25 °C is ordinarily below 10 mPa·s for a 6% solution when measured by rotational viscometer at 20 rpm. The granulation endpoint in a high-shear granulator must be re-optimized compared with povidone K30 because HES 130/0.4 produces less tack and a longer wet massing window. Tablets prepared with 2–4% w/w HES 130/0.4 as binder show acceptable disintegration below 15 min in deionized water at 37 °C when tested according to USP <701>, but friability may exceed 1.0% if the binder concentration is below 2% or if the granule moisture at compression is below 1.5% w/w. For capsule filling, spray-dried agglomerates with a D50 between 80 µm and 140 µm and a Hausner ratio below 1.25 are preferred; milled powders with higher fines require forced-feed capsule equipment to control weight variability. Because HES 130/0.4 is water-soluble and may form a gel layer, disintegration of tablets with high binder levels can be delayed; a disintegrant such as croscarmellose sodium at 2–4% w/w is typically co-processed. Storage below 25 °C and 60% RH is required because the powder is hygroscopic and moisture uptake above 10% w/w may cause caking and microbial proliferation.

In production-scale spray drying of starch derivatives, inlet air temperatures between 140 °C and 180 °C are common; outlet air temperature is maintained below 80 °C to avoid excessive moisture loss and particle fusion. Batch-to-batch variation in the acid hydrolysis endpoint is a recognized source of molecular weight distribution drift, and at-scale blending of sublots is often required to meet the 110 000–150 000 Da Mw window. The product should not be dry-compacted at high pressure without a plasticizer because the amorphous polymer can undergo brittle fracture and generate fines that worsen die filling and tablet weight uniformity.

What Limits Injectable Formulation pH, Endotoxin, and Particulate Control?

For injectable compounding, HES 130/0.4 is dissolved in Water for Injection containing 0.9% w/v sodium chloride to a final polymer concentration of 6% w/v. The solution is heated to 60–70 °C under low-shear mixing to accelerate hydration without extensive foaming. Before sterile filtration, the pH is adjusted to 4.0–5.5 with hydrochloric acid or sodium hydroxide; this pH range is selected because alkaline conditions accelerate oxidative degradation and hydrolysis of the hydroxyethyl ether groups. The colloid osmotic pressure of a 6% solution is verified by membrane osmometry at 25 °C; label data for HES 130/0.4 in 0.9% saline indicate values near 36 mmHg. A 0.45 µm prefiltration is followed by a 0.22 µm sterilizing-grade polyethersulfone membrane; the solution must meet the sub-visible particle limits of Ph. Eur. 2.9.19 and USP <788> after filtration.

Terminal steam sterilization at 121 °C for 15 min is not automatically interchangeable with aseptic filtration because the thermal process can hydrolyze glycosidic bonds and shift the molecular weight distribution downward. Published data for specific terminal sterilization configurations are limited, so any terminally sterilized formulation requires re-validation of Mw, molar substitution, pH, and colloid osmotic pressure after the maximum thermal exposure. For injectable use, the API is released with bacterial endotoxin limits derived from the maximum adult dose and the 5 EU/kg/h threshold in USP <85>; the finished product is tested before release with Ph. Eur. 2.6.14. The formulation is incompatible with excessive shear during mixing because high-shear homogenization may mechanically degrade the branched amylopectin backbone, increasing low-molecular-weight fragments and reducing volume-expanding efficacy. The labeled maximum daily dose for HES 130/0.4 in hypovolemia is commonly 50 mL/kg body weight, but the exact limit must follow the approved product label.

Compared with higher molecular weight hydroxyethyl starch grades, the 130/0.4 grade is eliminated more rapidly from plasma because its molecular weight distribution contains fewer chains above the renal threshold. The lower molar substitution also decreases tissue persistence because alpha-amylase can cleave the hydroxyethyl starch more readily than a 0.7-substituted product. This distinction matters in injectable use where repeated dosing of higher-substituted grades is associated with greater tissue accumulation. In oral use, the same property reduces gel strength and may require higher binder concentrations or additional dry binders.

Residual Solvent, Elemental Impurity, and Documentation Boundaries for a Dual Oral–Injectable API

The API is manufactured under current good manufacturing practice and is accompanied by a drug master file or active substance master file. Residual solvents are controlled under ICH Q3C; ethylene glycol, a Class 2 solvent, is a critical target because it is carried through from the hydroxyethylation reaction. The release limit for ethylene glycol must be derived from the permitted daily exposure of 6.2 mg/day and the maximum intended daily dose of the finished oral or injectable product. If the injectable dose is 50 mL/kg of a 6% solution for a 70 kg adult, the HES dose is approximately 210 g/day, which requires a tight residual solvent specification. Heavy metals and elemental impurities are managed under ICH Q3D; arsenic, cadmium, lead, and mercury are controlled based on the injectable route because oral and parenteral limits differ. Nitrosamine risk is considered low for hydroxyethyl starch due to the absence of secondary amines in the polymer backbone and the non-nitrosating conditions of manufacturing, but the manufacturer’s risk assessment should be available.

Residual peroxide from oxidative processing, if used, should be controlled because peroxide can generate oxidative chain scission during storage and reduce molecular weight. Residual sodium chloride and sodium acetate are controlled by conductivity and loss on ignition. For injectable use, the material is supplied in low-endotoxin packaging with double polyethylene liners inside sealed fiber drums; a retest period of 24 months from the date of manufacture is common when stored at 15–25 °C and protected from moisture. For oral use, the same API can be released under oral microbiological limits, but injectable-endotoxin-release material may be used for oral products when a single inventory is required. A single batch released against the injectable endotoxin limit can be used for oral formulations only when the oral formulation’s daily dose does not exceed the parenteral-derived limit.