| HS Code | 169444 |
| Product Name | SH-MDI Pharma Grade API |
| Product Code | SH-MDI |
| Grade | Pharma Grade |
| Api Type | Active Pharmaceutical Ingredient |
| Dosage Forms | Tablet, Capsule, Granule, Injection |
| Routes Of Administration | Oral, Injectable |
| Appearance | White to off-white crystalline powder |
| Assay | ≥ 99.0% (HPLC) |
| Solubility | Soluble in water; slightly soluble in organic solvents |
| Storage | Store in a cool, dry, well-ventilated place away from light and moisture |
| Shelf Life | 24 months from date of manufacture |
| Packaging | 25 kg fiber drum with double polyethylene inner bags |
| Regulatory Compliance | USP/EP/BP/JP |
| Application | Manufacture of oral and injectable pharmaceutical dosage forms |
| Hs Code | 2942000000 |
As an accredited SH-MDI 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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Where direct compression is the preferred route for SH-MDI pharma grade tablets, blend design is controlled around segregation potential and ejection force rather than only API assay. A representative direct compression batch is prepared by screening SH-MDI pharma grade with silicified microcrystalline cellulose (Prosolv SMCC HD 90) and crospovidone (Kollidon CL) through a 0.8 mm conical sieve, blending in a 600 L bin blender at 10 rpm for 15 min, and then lubricating with sodium stearyl fumarate at 0.75 wt% for 3 min. The lubricant choice avoids dissolution slowdown associated with magnesium stearate above 1.0 wt% when the API is hydrophobic. Powder flow is assessed under USP <1174>; a Hausner ratio above 1.30 or Carr index above 25% disqualifies the blend for direct compression and shifts the batch to roller compaction. Tablet compression is run on a 47-station Euro B rotary press with 10 mm flat-face bevel-edge tooling at 8–14 kN compression force and turret speed up to 70 min-1; ejection force values above 1,200 N are treated as a batch-processing fault because they indicate die-wall lubrication failure and are associated with tableting line stoppages on production-scale equipment. Hardness is kept between 60 N and 120 N to avoid lamination while preserving disintegration below 15 min. Content uniformity follows USP <905> and dissolution is tested according to USP <711> apparatus 2 at 50 rpm in 900 mL of pH 6.8 phosphate buffer. When ambient relative humidity exceeds 60%, the milled API is pre-dried in a vacuum dryer at 40°C for 4 h before blending because moisture pick-up above 0.5 wt% increases punch sticking and visible picking on this formulation type.
In high-shear wet granulation of SH-MDI pharma grade, impeller torque and chopper current are used to define the endpoint rather than visual dough texture. The dry phase contains SH-MDI pharma grade, mannitol, pregelatinized starch, and croscarmellose sodium; a 5% w/w hypromellose E5 binder solution is added at 25–35% w/w over 4–6 min in a 150 L high-shear granulator with impeller speed 300–500 rpm and chopper 1,500–3,000 rpm. Torque rise beyond 15% above baseline marks the transition to over-granulation, which produces dense granules that resist wet sieve transfer and increase subsequent tablet weight variation. The wet mass is discharged through a 6 mm screen and dried in a fluid-bed drier at inlet temperature 55–65°C until loss on drying reaches 1.5–2.5% w/w. Dried granules are milled through a 1.0 mm oscillating sieve and blended with sodium starch glycolate before compression. The granule size target is a D50 of 150–250 µm with fines below 75 µm limited to 25% because excess fines raise die-fill variation on high-speed presses. Tablet weight difference and disintegration are checked under USP <905> and USP <701>; dissolution is assessed with USP <711>. Production-scale batch-to-batch variance in this route is dominated by water addition rate and binder temperature; a change of 2°C in binder solution can shift granule D50 by more than 20 µm, which is observable as a change in press charge level and requires feeder speed adjustment. For oral granule presentations, the dried granules are filled into sachets instead of compressed; the same granule size target applies, but moisture is held below 1.0% to prevent clumping in high-humidity distribution climates.
Capsule filling lines running above 75,000 units/h impose different plug-formation and lubrication requirements on SH-MDI pharma grade than direct compression. A size 3 hard gelatin capsule containing 40 mg SH-MDI pharma grade is filled with a blend of spray-dried lactose, microcrystalline cellulose, crospovidone, and colloidal silicon dioxide; magnesium stearate is limited to 0.5 wt% because levels above this value delay capsule disintegration in USP <701> testing. On a dosator-type encapsulator, powder bed height is maintained at 120–140 mm, and the dosator compression height is adjusted to give plug density between 0.65 g/mL and 0.80 g/mL, which reduces weight variation without causing plug ejection defects. Weight uniformity follows USP <905>, and dissolution follows USP <711> apparatus 1 at 100 rpm in 900 mL of 0.1 N HCl for acid-stage release, with a second stage in pH 6.8 buffer when enteric protection is not used. Line stoppages on production-scale machines are most frequently traced to dosator nozzle blocking when relative humidity falls below 20%; addition of 0.1 wt% colloidal silicon dioxide and humidification to 40–50% RH restore plug compressibility and avoid static adhesion. When ambient humidity exceeds 55%, capsule shell softening increases rejection at the capsule sorting stage, and the filling suite is held at 21–24°C with dew point below 10°C.
Roller compaction of SH-MDI pharma grade is used when the API or blend is moisture-sensitive or when direct compression flow is insufficient. The blend is composed of SH-MDI pharma grade, microcrystalline cellulose, lactose monohydrate, crospovidone, and colloidal silicon dioxide; magnesium stearate is added at 0.25 wt% before compaction to prevent roll sticking. Compaction is performed on an Alexanderwerk WP 120 with roll diameter 120 mm, hydraulic pressure 80–120 bar, roll speed 5–15 rpm, and gap 2–4 mm. Ribbon solid fraction is maintained between 0.60 and 0.70; below 0.60 the granulate is too friable and produces excessive fines, while above 0.70 the milled granules are hard and resist disintegration. The ribbon is milled through an oscillating sieve with 0.8 mm aperture and optionally a 1.25 mm pre-screen. Granule size distribution after milling shows D50 of 180–280 µm and less than 20% fines below 75 µm. Tableting is performed at 10–16 kN, and tablets are tested under USP <905> and USP <711>. A known processing conflict in dry granulation is the trade-off between ribbon density and API dissolution: raising hydraulic pressure to improve yield can reduce dissolution below 80% at 30 min if the ribbon solid fraction exceeds 0.70, so the roll pressure window is narrower than for high-dose APIs. The granulate is also evaluated for bulk density before tableting; values below 0.45 g/mL result in die fill variation on high-speed presses.
| Dosage form | Test | Standard | Condition | Acceptance window |
|---|---|---|---|---|
| Direct compression tablet | Uniformity of dosage units | USP <905> | 10 units | AV ≤ 15 |
| Direct compression tablet | Dissolution | USP <711> | Apparatus 2, 50 rpm, pH 6.8 | Q = 80% at 30 min |
| Wet granule sachet | Loss on drying | USP <731> | 105°C | ≤ 2.5% |
| Capsule | Weight variation | USP <905> | 10 capsules | RSD ≤ 7.5% |
| Dry granule tablet | Disintegration | USP <701> | 37°C water | ≤ 15 min |
A sterile injectable presentation of SH-MDI pharma grade shifts the control burden from powder flow to sterility, endotoxin, particle size, and reconstitution. The API is dissolved or suspended in a buffered vehicle containing mannitol as a bulking agent, trehalose as a lyoprotectant, and pH-adjusted water for injection; the solution is passed through a 0.22 µm PVDF membrane filter and filled into 5 mL Type I borosilicate vials under Grade A laminar flow. Lyophilization is performed after freezing at -40°C for 2 h, primary drying at shelf temperature -20°C and chamber pressure 0.2 mbar, and secondary drying at 20°C until residual moisture is below 1.0%. Collapse temperature is verified by freeze-drying microscopy and differential scanning calorimetry before scale-up because published full-scale lyophilization data for this specific configuration is limited. The finished cake is tested under USP <1>, USP <85>, and USP <788>. Reconstitution time with 2 mL sterile water for injection should be under 2 min; cake collapse or high residual moisture above 1.0% triggers batch rejection because it alters reconstitution and possibly the API polymorphic form. Terminal sterilization is not applied if the API degrades under moist heat; in that case aseptic filtration is accompanied by pre-filtration bioburden below 10 CFU/100 mL and filter integrity testing before and after use.
Filtration of SH-MDI-containing sterile solutions is constrained by membrane binding, viscosity, and pre-filter pressure decay rather than by the chemical stability of the API alone. A 0.45 µm polyethersulfone prefilter is installed upstream of a 0.22 µm PVDF final filter to reduce bioburden and protect the final membrane; pressure differential is maintained below 0.5 bar across the final filter to avoid particle breakthrough and membrane damage. Throughput per 10-inch cartridge is monitored by total protein-binding capacity and clogging behavior, and production batches are filtered at 20–25°C to reduce viscosity-related flow decay. Filter integrity testing is performed by forward-flow or bubble-point method before filling and after filling under the filter manufacturer's technical bulletin and batch records. Terminal sterilization by autoclaving at 121°C for 15 min is acceptable only when forced degradation studies demonstrate assay loss below 2% and related substances remain within the specification; where the API is thermolabile, aseptic processing with sterilizing-grade filtration remains the default. In injectable manufacturing suites, microbial control follows ISO 14644-1 class 5 at rest and EU GMP Annex 1 Grade A, with settle plates below 1 CFU/4 h and contact plates below 1 CFU/plate.
| Test | Standard | Condition | Acceptance window |
|---|---|---|---|
| Sterility | USP <71> | 14 days incubation | No growth |
| Bacterial endotoxin | USP <85> | LAL kinetic chromogenic | ≤ 0.5 EU/mg |
| Particulate matter | USP <788> | Light obscuration | ≥ 10 µm ≤ 6,000/container; ≥ 25 µm ≤ 600/container |
| Residual moisture | USP <921> | Karl Fischer | ≤ 1.0% |
| Reconstitution time | Internal | 2 mL WFI | ≤ 2 min |
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SH-MDI Pharma Grade API is a single-entity active pharmaceutical ingredient supplied under the product code SH-MDI for formulation into tablets, capsules, granules, oral liquids, and injectable preparations. The product is released as a white to off-white crystalline powder and contains no binders, disintegrants, preservatives, or processing aids. The model designation SH-MDI identifies the active substance; alternative salt, hydrate, or solvate forms are not implied unless the lot certificate of analysis states otherwise. Storage is assigned in airtight, light-resistant containers at a temperature not exceeding 25 °C and relative humidity not exceeding 60% unless the approved specification requires more restrictive conditions.
Where no individual monograph for the chemical entity exists in USP, Ph. Eur., JP, or IP, the release specification is established under ICH Q6A and includes appearance, identification by infrared spectroscopy or chromatographic retention time, assay, related substances, residual solvents, water content by Karl Fischer titration, residue on ignition, elemental impurities, particle-size distribution, and microbiological quality appropriate to the intended route of administration. The product is not a finished dosage form; formulation development is required for every target product profile.
For tablet, capsule, and granule applications, the oral-grade material is controlled for particle-size distribution by laser diffraction under USP <429>. A D90 of ≤75 µm is commonly assigned when content uniformity in direct compression is critical. Bulk and tapped density are measured under USP <616> Method I, with representative bulk density in the range 0.35–0.55 g/mL and tapped density in the range 0.45–0.70 g/mL. These values support die filling on rotary tablet presses; powder flow should be assessed separately under USP <1174> because compendial density data alone do not predict flow.
The limits shown in the matrix are representative release criteria for a pharmacopoeial-grade active substance; the approved product specification in the regulatory dossier governs each batch. Validation of the HPLC assay includes specificity, linearity, and accuracy per ICH Q2(R1). System suitability criteria, such as resolution between the API and specified impurity peaks, are established in the monograph or manufacturer’s method.
| Parameter | Method | Oral solid dosage limit | Injectable grade limit |
|---|---|---|---|
| Appearance | Visual examination | White to off-white crystalline powder | White to off-white crystalline powder |
| Assay (HPLC) | USP <621> / Ph. Eur. 2.2.29 | 98.0–102.0% on dried basis | 98.0–102.0% on dried basis |
| Related substances | HPLC | Total ≤0.5%; unspecified ≤0.10% | Total ≤0.3%; unspecified ≤0.08% |
| Water content | USP <921> Method Ia | ≤0.5% | ≤0.3% |
| Residue on ignition | USP <281> | ≤0.1% | ≤0.1% |
| Bacterial endotoxins | USP <85> | Not required for non-sterile oral use | ≤0.25 EU/mg when used parenterally |
| Sterility | USP <71> | Not required | Meets sterility if claimed as sterile injectable grade |
| Particle size D90 | USP <429> | ≤75 µm | ≤20 µm |
| Bulk density | USP <616> Method I | 0.35–0.55 g/mL | Report result |
For hard-gelatin capsule filling, blend flow is the primary constraint. Tamping-pin machines require stable plug height at a compression thickness of 2–4 mm; blends with Carr index above 30% typically produce plug weight variability. A bulk density target of 0.45–0.65 g/mL supports consistent plug formation. If the API density falls outside this range, adjustment with lactose monohydrate or microcrystalline cellulose is used.
In granulation processes, the oral-grade powder is typically charged to a high-shear mixer with impeller tip speed in the range 4–8 m/s and wet massed with purified water or a binder solution. Over-wetting and tip speeds above 8 m/s may produce granules with a median size above 850 µm, which can reduce tablet hardness and extend disintegration times. Drying in a fluid-bed dryer is typically performed with inlet air temperature between 50 °C and 70 °C; exposure above this range has been associated with physical instability in similar crystalline APIs. Loss on drying after granulation is monitored by USP <731> and is held at or below 0.5% before compression.
The injectable-grade presentation is not a finer particle-size lot of the oral solid grade without further control. Sterile-filtration compatibility, endotoxin burden, and sub-visible particulate load are controlled from the crystallization and drying steps through final packaging. Bacterial endotoxin testing is performed under USP <85>; a representative acceptance criterion is ≤0.25 EU/mg when the API is intended for parenteral administration. The actual limit is derived from the maximum total daily dose using the formula K/M, where K is 5 EU/kg body weight for parenteral products and M is the maximum dose in units per kilogram per hour.
Sterility testing is required only when the injectable-grade API is claimed as sterile. USP <71> membrane filtration is used, with validation of bacteriostasis and fungistasis. For non-sterile API intended for terminal sterilization, the API is not required to meet sterility; however, bioburden control before sterile filtration or autoclaving is critical. Production-scale experience indicates that microbial load above 10 CFU/g can reduce the sterility assurance level of a 0.22 µm sterilizing-grade filter, particularly when the product stream contains visible particulate matter.
Particle-size limits for injectable-grade material are tighter than for oral solid forms. A D90 of ≤20 µm is often assigned to facilitate uniform suspension or dissolution. Sub-visible particulate matter in the finished injectable is evaluated by USP <788> for large-volume parenterals or USP <789> for small-volume parenterals; the API itself is not tested by these methods, but the particle-size distribution and insoluble residue contribute to the finished-product result.
For lyophilized injectable formulations, the API is dissolved with a bulking agent such as mannitol or trehalose and filled as a solution. Residual moisture after freeze-drying is controlled to ≤1.0% by USP <921> Method I, and the cake appearance is assessed for collapse. Injectable-grade material with low endotoxin and controlled sub-visible particles reduces the burden on the final sterile filtration step.
For oral liquid preparations, the API is dissolved or suspended in a vehicle according to the formulation. Microbiological quality of the non-sterile oral liquid is controlled under USP <1111>, with a total aerobic microbial count not exceeding 10³ CFU/g and a total yeast and mold count not exceeding 10² CFU/g. Absence of Escherichia coli is required where water-containing oral preparations are concerned. The API used for oral liquids is not required to meet parenteral endotoxin or sterility limits; however, residual solvent and elemental impurity controls remain in force.
Direct compression is selected only when the powder blend demonstrates a flow function coefficient greater than 4.0 and a Carr index below 23%. For brittle crystalline APIs, a Heckel yield pressure below 150 MPa typically indicates acceptable plastic deformation; higher yield pressures may require a ductile filler or wet granulation. At compression forces from 8 kN to 20 kN on a rotary tablet press, a brittle fracture index above 0.5 can increase capping risk at turret speeds above 50 rpm.
Field data from similar high-shear and direct-compression platforms show that segregation in the feed frame occurs when the API D90 exceeds 90 µm and the bulk density difference between API and filler exceeds 0.2 g/mL. Tablet weight variability then exceeds 3% relative standard deviation. Maintaining the API D90 at or below 75 µm reduces this variability, but excessive fines below 45 µm can lower powder flow and increase punch filming. A controlled particle-size distribution with D10 not less than 10 µm and D90 not more than 75 µm balances these risks.
Pre-drying at 40–50 °C for 12–24 h is required if water content by USP <921> Method Ia exceeds 0.5% or ambient relative humidity is above 60%. Moisture can increase sticking in the die bore and reduce tablet tensile strength. The use of magnesium stearate as a lubricant should be limited to 0.25–1.0% w/w with blend times of 3–5 min; over-lubrication can delay disintegration and slow dissolution.
The main process conflict in solid oral development is the relationship between particle-size reduction and flow. Jet milling to reduce D90 below 20 µm can improve dissolution for low-solubility APIs but may reduce flow and increase triboelectric charging. For direct compression, this trade-off is managed by blending with flow agents such as colloidal silicon dioxide at 0.5–1.5% w/w. Wet granulation resolves flow but introduces a drying step and may convert crystalline material to a partially amorphous state; the amorphous fraction is controlled by X-ray powder diffraction and should not exceed 5% unless stability data support otherwise.
Residual solvent testing follows ICH Q3C. Class 1 solvents such as benzene and carbon tetrachloride are controlled at not more than 2 ppm and 4 ppm, respectively, or are absent at release. Class 2 solvents such as methanol, dichloromethane, and toluene are limited to their permitted daily exposure values; for a 10 g daily dose, the corresponding concentration limits are calculated from the PDE. Class 3 solvents are limited to 0.5% w/w, consistent with standard pharmaceutical practice.
Elemental impurities are controlled under ICH Q3D by risk assessment. A parenteral route requires lower permitted daily exposures than an oral route for elements such as cadmium, lead, arsenic, and mercury. For a parenteral product, the PDE for lead is 5 µg/day, for cadmium 2 µg/day, for arsenic 15 µg/day, and for mercury 3 µg/day; these values are not release limits but serve as calculations for concentration limits based on daily dose. Inductively coupled plasma mass spectrometry after microwave digestion is used to quantify the elemental impurity profile.
For mutagenic impurities, ICH M7 applies when structural alerts or process impurities are present. A threshold of toxicological concern of 1.5 µg/day is used for control; a compound-specific acceptable intake may be higher or lower. Where the synthetic route uses sulfonate esters or nitrosating conditions, analytical methods with limits of quantification below 1 ppm are required. Published data for this specific configuration is limited; therefore, the control strategy is derived from the registered impurity profile and process validation.
Operationally, the API should not be exposed to open air above 60% relative humidity for more than 8 h. Combination with strong oxidizing agents is avoided because of degradation risk. If a nitrogen-blanketed handling system is used, the oxygen level is held below 5% for extended storage of opened containers.
Differences from uncontrolled technical-grade material or non-pharmacopoeial sources are material. SH-MDI Pharma Grade API is manufactured under a pharmaceutical quality system aligned with ICH Q7 and 21 CFR 211.84 receiving controls. Technical-grade material may contain residual catalysts above parenteral PDE limits, may not be tested for nitrosamines or sulfonate esters under ICH M7, and is not traceable through change control or batch disposition records. The oral solid grade and injectable grade are distinguished by particle-size ceiling, endotoxin control, microbial quality, and packaging; they are not interchangeable without requalification under the approved marketing authorization. The product code SH-MDI should not be confused with industrial methylene diphenyl diisocyanate; this designation is used here solely as the manufacturer’s pharmaceutical API code.
