| HS Code | 535956 |
| Productname | Low-substituted hydroxypropyl cellulose/LHPC Pharma Grade API for Tablet/Capsule/Granule/Injection, Oral & Injectable |
| Synonyms | L-HPC; LHPC; Low-substituted hydroxypropylcellulose |
| Chemicalname | Low-substituted hydroxypropyl cellulose |
| Chemicalclass | Cellulose ether |
| Casnumber | 9004-64-2 |
| Einecs | 618-389-9 |
| Molecularformula | Variable polymeric cellulose ether |
| Molecularweight | Variable |
| Appearance | White to off-white powder |
| Odor | Odorless |
| Taste | Tasteless |
| Form | Powder |
| Solubility | Insoluble in water, ethanol, and acetone; swells in water; soluble in dilute sodium hydroxide |
| Ph | 5.0-7.5 (1% aqueous suspension) |
| Moisturecontent | <=5.0% |
| Lossondrying | <=5.0% |
| Residueonignition | <=0.5% |
| Heavymetals | <=10 ppm |
| Arsenic | <=2 ppm |
| Assay | 98.0-102.0% |
| Hydroxypropoxycontent | 7.0-12.9% |
| Degreeofsubstitution | 0.2-0.4 |
| Viscosity | 5-20 mPa.s (2% dispersion, 20 C) |
| Particlesize | D50 20-50 micrometers; typically 90% < 100 micrometers |
| Bulkdensity | 0.3-0.6 g/mL |
| Tappeddensity | 0.5-0.8 g/mL |
| Swellingcapacity | High swelling in water |
| Flowability | Good |
| Angleofrepose | <=40 degrees |
| Function | Disintegrant, binder, matrix former, stabilizer |
| Application | Tablets, capsules, granules, oral and injectable formulations |
| Routeofadministration | Oral; Injectable |
| Grade | Pharma Grade API |
| Regulatorystandards | USP/NF, EP, JP, ICH Q7 |
| Manufacturingmethod | Reaction of alkaline cellulose with propylene oxide |
| Storage | Store in a cool, dry, well-ventilated place away from moisture |
| Shelflife | 24 months |
| Packaging | 25 kg fiber drum with double polyethylene liner |
| Hs Code | 3912.39.00 |
| Stability | Stable under normal storage conditions |
| Hygroscopicity | Hygroscopic; protect from moisture |
| Microbiallimits | Total aerobic count <=1000 cfu/g; yeast/mold <=100 cfu/g; absence of E. coli and Salmonella |
As an accredited Low-substituted hydroxypropyl cellulose/LHPC 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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In high-dose direct compression lines running 10 mm round biconcave tooling on a 34-station rotary tablet press equipped with a force feeder, low-substituted hydroxypropyl cellulose (L-HPC; USP-NF monograph for Low-Substituted Hydroxypropyl Cellulose) is dry-blended as a binder-disintegrant at 5%–20% w/w, with the lower range applied when pregelatinized starch or crospovidone is present and the upper range applied for poorly compressible actives. Blending is carried out in a 600 L bin blender at 8–12 rpm for 15–25 minutes, followed by magnesium stearate addition at 0.25%–0.75% w/w with a lubrication step limited to 3–5 minutes because overlubrication increases disintegration time under USP <701> beyond the 15-minute limit for immediate-release tablets. Compression force is maintained between 8 kN and 20 kN with precompression at 4–6 kN; in-process tablets are checked against USP <1216> friability at ≤1.0%, USP <905> content uniformity, and USP <711> dissolution using the specified medium for the active monograph. Grade selection follows particle size: LH-11, with a mean particle diameter near 50 µm, reduces segregation in high-dose blends, while LH-31 with a mean particle diameter near 25 µm accelerates wicking but may reduce flow, measured as compressibility index under USP <1174>. Terminal finished product type is immediate-release oral tablet. Parenteral or injectable finished products remain outside the validated application envelope of L-HPC because the water-insoluble particulate load is incompatible with injectable limit tests and no pharmacopeial monograph supports L-HPC in parenteral formulations. Production-scale failure observations include capping when precompression force falls below 4 kN or when residual moisture after storage is below 2.0%, particularly in brittle excipient matrices.
Low-substituted hydroxypropyl cellulose is incorporated intragranularly in high-shear mixer-granulators at 5%–15% w/w of the dry solids, with an additional extragranular split of 2%–5% w/w reserved for post-milling disintegration. The granulation process uses purified water as binder fluid; impeller speed is set between 150 rpm and 300 rpm, chopper speed at 1,500 rpm, and wet massing time is terminated when impeller power consumption reaches a predetermined torque endpoint or after 2–5 minutes. Wet granules are dried in a fluid-bed dryer at inlet air temperature 60°C–75°C and product temperature 40°C–45°C, with loss on drying controlled to 1.5%–3.0% per USP <731>. Dried granules are screened through a 0.8 mm conical mill at 1,500 rpm to produce a 20–60 mesh granule fraction. The addition ratio and granulation endpoint directly affect compressed-tablet disintegration; overgranulation densifies the L-HPC phase and reduces wicking, which can push USP <701> disintegration beyond 15 minutes for immediate-release products. Compliance for this operation invokes USP-NF monograph identity and purity for L-HPC, USP <905> uniformity of dosage units, USP <711> dissolution, ICH Q3D elemental impurities, and ICH Q3C residual solvents when hydroalcoholic binder solutions are used. Terminal finished product type is immediate-release tablet produced from wet-milled granule intermediate. Equipment-related failure modes observed on production scale include overwet mass sticking to the granulator bowl and torqued impeller load fluctuation when L-HPC content exceeds 15% w/w in formulations containing microcrystalline cellulose above 30% w/w. Alcohol-water granulating fluids above 20% ethanol are not recommended because L-HPC swells less uniformly in high alcohol fractions, producing broad granule particle size distributions.
For roller-compacted dry granulation lines, L-HPC is integrated at 5%–10% w/w intragranularly and 2%–5% w/w extragranularly because plastic deformation of the polymer under roll pressure consumes part of the swelling capacity that would otherwise produce tablet disintegration. A production-scale roller compactor with roll force 8–15 kN/cm, roll speed 5–15 rpm, and roll gap 1.0–2.5 mm produces ribbons of target density 0.9–1.2 g/cm³; ribbons are then screened through a 0.8–1.25 mm oscillating or conical mill at 1,000–1,500 rpm. The milled granule fraction between 18 mesh and 60 mesh is blended with remaining extragranular L-HPC and lubricant before compression on a rotary tablet press at 8–18 kN. The major process conflict is that increasing roller compaction force improves granule flow and reduces segregation but lowers the disintegrant efficiency of intragranular L-HPC; therefore, disintegration under USP <701> is monitored for each roller force setting, and dissolution under USP <711> is performed on the finished batch because the dense ribbon core may release active more slowly than direct compression blends. Compliance requires USP-NF Low-Substituted Hydroxypropyl Cellulose monograph conformance, USP <905> content uniformity, USP <1216> friability at ≤1.0%, and ICH Q3D elemental impurity control. Terminal finished product type is immediate-release tablet or granule-filled hard capsule from roller-compacted granule. Production-line equipment data show that roll force above 15 kN/cm on L-HPC/lactose matrices can produce ribbons too rigid for consistent screening and yield a bimodal granule size distribution with fines below 100 µm causing die-fill variation. Published data for this specific configuration are limited, so roll force and roll gap must be qualified per formulation and active load.
In hard capsule filling of immediate-release formulations, L-HPC is incorporated at 2%–10% w/w of the powder blend to function as a wicking and swell-induced disintegrant within the compacted powder plug formed by a dosator or tamping-pin filler. The blend is prepared in a low-shear drum blender at 6–12 rpm for 15–25 minutes; magnesium stearate is limited to 0.25%–1.0% w/w and blended for 3–5 minutes because higher levels retard water penetration and mask the swelling of L-HPC. Capsule fill weight is controlled to ±3% relative standard deviation during 70,000–120,000 capsules/hour dosator filling; plug compression force is adjusted between 15 N and 40 N to avoid plug fracture or powder fall-out. USP <701> disintegration is run with discs on capsules in 37°C purified water, and dissolution is run per USP <711> for the active monograph; uniformity of dosage units follows USP <905>. The L-HPC grade is typically LH-21 because its intermediate particle size balances flow and rapid wicking. Terminal finished product type is hard-shell gelatin or HPMC capsule. A production-scale failure mode occurs when encapsulation speed is increased without adjusting plug compression: low plug strength causes capsule splitting or prolonged disintegration due to dense plugs. The combination of L-HPC with sodium starch glycolate in capsule formulations above 8% w/w total superdisintegrant may reduce powder flow and increase fill-weight variability, but no absolute incompatibility is established. Storage below 40% RH is not required for L-HPC itself, but hard gelatin capsules require moisture control to prevent shell brittleness.
Orally disintegrating tablet (ODT) manufacture with L-HPC uses 3%–10% w/w of the tablet weight together with mannitol or lactose-based filler blends and microcrystalline cellulose below 20% w/w. Compaction is performed on a rotary tablet press with 8 mm flat-faced bevel-edge tooling at main compression force 5–12 kN and precompression 2–4 kN; tablet hardness is maintained between 20 N and 40 N, and friability remains below 1.0% under USP <1216>. In-process disintegration time per USP <701> is targeted below 30 seconds in 37°C purified water, consistent with the FDA guidance for orally disintegrating tablets. Higher compression force improves hardness and reduces friability but pushes disintegration beyond 60 seconds when L-HPC is the only disintegrant; therefore, the process window is narrow and is verified by a force-hardness-disintegration matrix across 3–5 N increments. The formulation is blended in a 100–300 L tumble blender at 10–15 rpm for 10–20 minutes, with lubrication by magnesium stearate below 0.5% w/w to avoid hydrophobic retardation of the fast wetting needed for oral disintegration. Compliance includes USP-NF L-HPC monograph, USP <905> content uniformity, USP <1216> friability, ICH Q3D elemental impurities, and ICH Q3C residual solvents if organic taste-masking solvents are used. Terminal finished product type is orally disintegrating tablet administered without water. Production-scale observations show friability failures cluster in the 2.0%–2.5% w/w L-HPC range when compaction force is below 7 kN, and tablet weight variation increases if feed shoe speed is not matched to the low bulk density of the L-HPC-containing blend.
Extrusion-spheronization pellet manufacture for multiparticulate hard capsule or unit-dose sachet filling integrates L-HPC at 10%–20% w/w of the dry solids as a binder-disintegrant with microcrystalline cellulose at 30%–50% w/w. The dry mix is wetted with purified water or water-ethanol below 20% ethanol in a planetary mixer; the wet mass is passed through a twin-screw extruder with L/D ratio 20:1 at screw speed 50–150 rpm, then spheronized on a cross-hatch plate at 800–1,200 rpm for 2–6 minutes. Pellets are dried in a fluid-bed dryer at inlet air 60°C–70°C to moisture ≤2.5%, then sieved to a 0.5–1.0 mm target fraction. The pellet batch is tested for sieve distribution, bulk density, and disintegration by USP <701>; finished multiparticulate capsules or sachets are tested for dissolution under USP <711> and content uniformity under USP <905>. Terminal finished product type is multiparticulate pellets filled into hard gelatin/HPMC capsules or unit-dose sachet stick packs. Compliance requires USP-NF Low-Substituted Hydroxypropyl Cellulose monograph conformance, ICH Q3D elemental impurities, and ICH Q3C residual solvents. Published data for this specific configuration are limited; the 10%–20% w/w addition range is derived from exploratory formulations rather than an established pharmacopeial monograph and must be verified against target drug release. Water levels above 45% w/w of the dry mass during granulation can produce sticky extrudate and spheronizer screen blockage, while water below 35% w/w can produce brittle extrudate and excess fines. These boundaries shift with the particle size of microcrystalline cellulose and drug solubility, so wet massing endpoint must be controlled by torque or plasticity rather than fixed water volume alone.
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Low-substituted hydroxypropyl cellulose (LHPC), CAS 9004-64-2, is a cellulose ether produced by reacting purified wood pulp or cotton linter cellulose with propylene oxide under controlled alkaline substitution. The term “low-substituted” refers to the hydroxypropoxy content, which compendial monographs place between 5.0% and 16.0% on the dried basis. LHPC is listed in USP/NF, Ph.Eur., and JP as Low-Substituted Hydroxypropyl Cellulose and appears in the FDA Inactive Ingredients Database for oral solid dosage forms. Although commercial listings may use the phrase “Pharma Grade API,” the material functions as a pharmaceutical excipient rather than an active pharmaceutical ingredient. In tablet, capsule, and granule applications, LHPC provides disintegration, dry binding, and anti-capping effects through a combination of fibrous particle entanglement, capillary wicking, and moderate swelling. Unlike fully substituted hydroxypropyl cellulose, which is water-soluble, LHPC remains practically insoluble in water but swells rapidly; this behavior is the basis for its use in immediate-release oral solid dosage forms.
The pharmacopoeial monograph for Low-Substituted Hydroxypropyl Cellulose sets the product apart from non-compendial cellulose ethers by imposing identity, purity, and assay controls that must be met before release to pharmaceutical manufacturing. Hydroxypropoxy content is the critical chemical marker: values below 5.0% approach unsubstituted cellulose and exhibit insufficient swelling, while values above 16.0% shift toward water-soluble HPC behavior and can produce gel-like films instead of discrete disintegrant particles. Loss on drying is controlled because moisture above 5.0% can impair powder flow and alter tablet hardness. Residue on ignition limits inorganic contamination from cellulose feedstock and process alkalis. Heavy metal limits are typically set at 20 µg/g or tighter for oral and injectable-grade material, and microbial limits follow USP <61> and USP <62>.
| Property | Compendial Acceptance Range | Reference Method |
|---|---|---|
| Appearance | White to off-white powder or granules | Visual inspection |
| Hydroxypropoxy content | 5.0%–16.0% | USP/NF monograph assay |
| Loss on drying | ≤5.0% | USP <731> |
| Residue on ignition | ≤1.5% | USP <281> |
| Heavy metals | ≤20 µg/g | USP <231> or regional equivalent |
| Microbial limits | Total aerobic microbial count ≤10³ CFU/g; molds/yeasts ≤10² CFU/g | USP <61>, USP <62> |
Residual propylene oxide and propylene chlorohydrin are controlled in the monograph because the synthetic route uses propylene oxide. Identification is confirmed by infrared absorption spectroscopy; the cellulose backbone hydroxypropyl ether bands are compared with a reference standard. Suppliers may also report particle-size distribution, tapped density, and peroxide levels on the certificate of analysis for specific model designations.
Commercial LHPC is not a single entity but a family of particle-size–defined grades. Supplier model designations such as LH-11, LH-21, and LH-31 are not pharmacopoeial names but manufacturer-specific codes for sieve-cut or air-classified products. Coarser fibrous grades are preferred for direct compression because they entangle with other particles and reduce tablet capping at low compression force. Fine grades are used in wet granulation or added extragranularly to generate many capillary channels without creating visible specks on the tablet surface. A typical laser diffraction D50 for commercial grades falls between 20 µm and 60 µm, and the D10 to D90 span is controlled to limit segregation. Because compendial monographs do not define particle-size models, batch selection must consider the supplier’s certificate of analysis and the target dosage form. Substitution of one LHPC model for another at equal weight may alter disintegration time, tablet hardness, or content uniformity; comparative testing according to USP <905> for content uniformity and USP <701> for disintegration is required.
In direct-compression tablet matrices, LHPC is typically used at 2% to 10% w/w as a disintegrant, and at 5% to 25% w/w when a dry binder function is also required. The disintegrant action proceeds by three mechanisms: capillary water uptake into the fibrous particle network, swelling of the partially substituted cellulose, and mechanical disruption of the compact as hydrated LHPC particles push against adjacent excipient domains. Disintegration testing is performed under USP <701> at 37±2 °C in purified water; tablet hardness is usually held between 6 kp and 10 kp for placebo formulations and between 8 kp and 14 kp for high-dose tablets. Formulations containing 5% w/w extragranular LHPC and compressed to 8 kp typically disintegrate within 5 min, whereas the same formulation with 2% w/w may remain intact for 10–15 min. The hardness–disintegration relationship is steeper than for crospovidone because LHPC contributes to compact strength; high compression force can delay disintegration unless the LHPC level is raised or the grade is shifted to a finer particle size.
The anti-capping benefit derives from the fibrous morphology of LHPC. In direct-compression runs on high-speed rotary presses with precompression, LHPC reduces the elastic recovery of brittle fillers and lowers ejection force when combined with 0.5% w/w magnesium stearate. The use level of magnesium stearate should be minimized because hydrophobic coating of LHPC particles can reduce water penetration and increase disintegration time beyond 15 min in USP <701> testing.
In wet granulation, LHPC is commonly used at 5% to 20% w/w and can be added entirely intragranularly or split between intragranular and extragranular phases. The intragranular fraction swells during aqueous granulation and acts as a binder; the extragranular fraction remains in the final blend and acts as a disintegrant after compression. Compared with croscarmellose sodium, LHPC shows lower equilibrium swelling and slower gel formation. This property reduces the risk of over-granulation blockages when high-shear granulation endpoints are extended or when water content rises above 25% w/w. Croscarmellose sodium can form highly swollen gel domains that restrict tablet pore networks after drying; LHPC retains a more open fibrous structure.
However, LHPC is not a direct functional substitute at equal weight. Croscarmellose sodium generally produces faster disintegration at low concentrations, but LHPC provides better dry binding and may lower granulation moisture sensitivity. High-shear mixer power consumption is also affected by the water-binding capacity of LHPC. Because LHPC swells rather than dissolves, granulation endpoint is less sensitive to small water additions; this is not the case with fully substituted HPC, which dissolves and increases granule viscosity sharply. Overwetting can still produce oversized granules and extended drying times. Comparative studies should be run with constant tablet hardness at 8 kp, granulation water content by USP <921>, dissolution by USP <711>, and disintegration by USP <701>. Published data for this specific configuration is limited; therefore direct substitution without process adjustment may increase disintegration time in harder tablets.
For hard-capsule filling, LHPC is incorporated into powder or granulation formulations to improve plug hardness and to disrupt the capsule plug after shell dissolution. Concentrations between 3% and 8% w/w are common in immediate-release capsule powders. In granule-filled sachets, LHPC can reduce lumping upon reconstitution by allowing liquid to penetrate the granule bed. Injectable and oral liquid applications require separate qualification. Because LHPC is water-insoluble, it does not form a clear solution and cannot be used as a conventional parenteral viscosity modifier. If injectable-grade use is intended, the material must pass particulate matter limits per USP <788>, bacterial endotoxins per USP <85>, and sterility per USP <71> after terminal sterilization. Published data for this specific configuration is limited; therefore injectable use should be preceded by supplier qualification for endotoxin and particulate release, and the formulation should be validated as a suspension rather than a solution.
The functional difference between LHPC and other disintegrants is best understood by separating swelling capacity, wicking rate, and moisture sensitivity. LHPC has moderate swelling and a strong fibrous wicking contribution; croscarmellose sodium has high swelling and forms gel-like structures; crospovidone has negligible swelling but rapid wicking; sodium starch glycolate has very high swelling but higher moisture sensitivity. The table below summarizes the typical use windows and mechanism differences. These ranges are not compendial specifications but formulation-use levels reported in excipient supplier literature and pharmacopoeial application notes.
| Disintegrant | Primary Mechanism | Typical Use Concentration | Key Difference from LHPC |
|---|---|---|---|
| Low-substituted hydroxypropyl cellulose | Fibrous wicking + moderate swelling | 2%–25% w/w | Dual dry binder/disintegrant, water-insoluble, fibrous |
| Croscarmellose sodium | Rapid swelling | 2%–5% w/w | Higher swelling, gel formation, no dry binding |
| Crospovidone | Capillary wicking | 2%–5% w/w | Non-swelling, rapid wicking, does not add compact strength |
| Sodium starch glycolate | Rapid swelling | 2%–8% w/w | Higher swelling, more moisture-sensitive, no fibrous binding |
| Pregelatinized starch | Swelling + partial gel | 5%–10% w/w | Disintegrant/binder but lower swelling than LHPC, may affect dissolution |
Dynamic vapor sorption at 60% relative humidity and 25 °C shows that LHPC gains less moisture than sodium starch glycolate and croscarmellose sodium, but more than crospovidone. This ranking matters in moisture-sensitive formulations such as effervescent powders or hydrolytically unstable actives. Because LHPC is a cellulose ether, it may contain trace peroxides; oxidation-sensitive actives require a peroxide-controlled grade and a stability study under ICH Q1A conditions at 40 °C/75% relative humidity. In such formulations, replacement of crospovidone with LHPC may require adjustment of the antioxidant package to prevent oxidative degradation. Published data for this specific configuration is limited.
In roller compaction, LHPC-containing powder is densified between counter-rotating rolls and then milled into granules. The retained disintegrant function depends on ribbon density, mill screen size, and the position of LHPC within the granule. If the roll force is set too high, LHPC particles undergo plastic deformation and lose the capillary void structure required for rapid water uptake. Milling through screens with apertures below 0.5 mm can produce fines that segregate during tableting, while screens above 1.0 mm can create coarse granules with poor content uniformity. Production-scale dry granulation lines typically monitor roll speed, roll force, gap width, and mill overload. For LHPC formulations, a split-feed approach—where part of the LHPC is added after milling—preserves extragranular disintegrant function.
Batch-to-batch variability in LHPC moisture can change ribbon density and granule size; therefore pre-drying at 105 °C for 20 min is applied when storage relative humidity exceeds 60%. Excessive specific compaction force can reduce disintegration performance; disintegration times may exceed 15 min when the ribbon density approaches the true particle density. Comparative batches should be tested for disintegration per USP <701>, dissolution per USP <711>, and tablet hardness per USP <1217>. Published data for this specific equipment configuration is limited beyond manufacturer processing guides; pilot-scale roller compaction is required before scale-up.
