(R)-Diphenylprolinol Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable
- Product Name: (R)-Diphenylprolinol Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable
- Factroy Site: Yudu County, Ganzhou, Jiangxi, China
- Price Inquiry: sales10@sinochem-nanjing.com
- Manufacturer: Ascent Petrochem Holdings Co., Limited
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- (R)-Diphenylprolinol Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable is typically used in formulations when enantiomeric purity and residual solvent levels must be controlled within specific ranges.
| HS Code | 605727 |
| Product Name | (R)-Diphenylprolinol Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable |
| Synonyms | (R)-alpha,alpha-Diphenyl-2-pyrrolidinemethanol; (R)-Diphenyl(pyrrolidin-2-yl)methanol; (R)-DPP; (R)-2-(Diphenylhydroxymethyl)pyrrolidine |
| Chemical Name | (R)-Diphenyl(pyrrolidin-2-yl)methanol |
| Chemical Class | Chiral amino alcohol |
| Cas Registry Number | 22348-32-9 |
| Molecular Formula | C17H19NO |
| Molecular Weight | 253.34 g/mol |
| Appearance | White to off-white crystalline powder |
| Purity | >=99.0% (HPLC) |
| Grade | Pharmaceutical Grade |
| Dosage Forms | Tablet, Capsule, Granule, Injection |
| Routes Of Administration | Oral, Injectable |
| Solubility | Soluble in organic solvents such as ethanol, methanol, and dichloromethane; slightly soluble in water |
| Melting Point | 76-80 °C |
| Optical Configuration | (R)-enantiomer |
| Storage Conditions | Store in a cool, dry place, protected from light and moisture |
| Stability | Stable under normal storage conditions |
As an accredited (R)-Diphenylprolinol 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.
| Packing | (R)-Diphenylprolinol Pharma Grade API supplied in 1 kg, 5 kg, and 25 kg sealed, light-resistant containers for oral and injectable use. |
| Container Loading (20′ FCL) | 20′ FCL loaded with (R)-Diphenylprolinol Pharma Grade API in sealed drums, palletized, for oral/injectable tablet, capsule, granule, and injection production. |
| Shipping | Shipping: (R)-Diphenylprolinol Pharma Grade API is transported in sealed, light-resistant, tamper-evident containers with desiccant. Ambient or temperature-controlled per stability data. Documents include COA, SDS, packing list. Labeled for oral and injectable use. Handled under GDP; avoid moisture, heat, contamination. Customs and regulatory documentation provided as required. Store and transport per manufacturer instructions. |
| Storage | Store (R)-Diphenylprolinol Pharma Grade API in a cool, dry, well-ventilated area, protected from light and moisture. Keep containers tightly closed, preferably under inert gas, and maintain a validated temperature—typically 2–8°C or 15–25°C per stability data. Segregate from oxidizers, acids, and incompatible materials. Follow cGMP, quarantine, and label instructions for oral and injectable use. Do not freeze unless validated. |
| Shelf Life | For (R)-Diphenylprolinol pharma-grade API, shelf life typically 24–36 months when sealed, light/moisture-protected, at controlled room temperature; verify supplier stability data. |
In tablet-directed production, (R)-diphenylprolinol is not a residual component of the finished tablet; it enters the campaign as a chiral auxiliary and is removed during workup. Its downstream role is therefore catalyst charging rather than final formulation content. At the point of enantioselective ketone reduction in a GMP intermediate train, the compound is charged to a glass-lined reactor as a Lewis-basic ligand that, upon contact with borane–tetrahydrofuran, forms the Corey–Bakshi–Shibata oxazaborolidine. Campaign batch records for tablet-directed API synthesis commonly specify a DPL charging ratio of 0.5–10 mol% relative to prochiral ketone, with borane–tetrahydrofuran complex maintained at 1.0–1.4 molar equivalents. The reduction is run in anhydrous tetrahydrofuran at a substrate concentration of 0.3–1.0 mol/L; the ketone solution is metered over 45–120 min while the internal temperature is held between -10 °C and 5 °C. A glass-lined reactor equipped with a 4-blade retreat-curve impeller and bottom discharge is used because the quench mass includes sodium chloride and boron salts that must be discharged without manual opening. The quench with 2 M hydrochloric acid is exothermic; acid addition is controlled to keep the liquid phase below 30 °C and to limit diastereomer formation. After phase separation, the organic layer is washed with 10% w/w sodium chloride solution, concentrated under vacuum at ≤45 °C, and crystallized from 6:1 v/v n-heptane/ethyl acetate. The resulting chiral secondary alcohol is converted to the final API, which is tableted at an API content of 5–25% w/w in a formulation containing microcrystalline cellulose 45–65% w/w, lactose monohydrate 20–35% w/w, crospovidone 2–5% w/w, and magnesium stearate 0.5–1.0% w/w. Tablet hardness is held at 40–80 N, friability below 0.8% w/w, and disintegration time below 15 min. Release obligations include ICH Q7 for API batch records, ICH Q3C for residual solvents, ICH Q3D for elemental impurities, USP <711> for dissolution, and USP <905> for content uniformity. Terminal product types are 10 mg, 20 mg, and 50 mg film-coated tablets. Water ingress above 1000 ppm in the reduction medium causes borane hydrolysis and enantiomeric excess loss; primary amine-containing impurities displace the ligand from the oxazaborolidine and must be absent from the ketone feed.
| Terminal dosage form | Manufacturing stage | Representative standards | Critical attribute controlled |
|---|---|---|---|
| Immediate-release tablet | API synthesis / tableting | ICH Q7, USP <711>, USP <905> | chiral purity not less than 98.0%, tensile strength 1.5–2.5 MPa |
| Hard gelatin capsule | Aldol reaction / capsule filling | ICH Q7, USP <701>, 21 CFR 211.165 | fill weight variation ±5%, disintegration ≤15 min |
| Oral granules | Fluid-bed granulation | ICH Q3C, USP <467>, USP <786> | loss on drying ≤2.0% w/w, D50 150–350 µm |
| Injection | Reduction / sterile filtration | ICH Q3D, USP <85>, USP <787> | residual DPL ≤0.10% w/w, particulate matter within compendial limits |
What Limits Residual Diphenylprolinol Clearance in Injectable API Streams After Borane-Mediated Reduction?
Injectable API campaigns are designed around a lower DPL charge of 1–2 mol% relative to ketone to reduce the removal burden in downstream liquid–liquid extraction. The reduction is conducted at -20 °C to 0 °C in tetrahydrofuran; after conversion, the reaction mixture is quenched with 1 M hydrogen chloride, diluted with methyl tert-butyl ether, and washed sequentially with 0.5 M hydrogen chloride, 5% w/v sodium bicarbonate, and water for injection. Residual DPL is measured by reverse-phase HPLC using a method validated under ICH Q2(R1); campaign targets for injectable-grade API are set at ≤0.10% w/w, although published data for this specific configuration is limited and the final limit is established through toxicological qualification rather than a harmonized monograph. Boron residues from the oxazaborolidine system are reduced by activated carbon treatment at 0.2–0.5% w/w for 30–60 min at 20–25 °C, followed by filtration through a 0.45 µm prefilter and a 0.22 µm sterilizing-grade PVDF membrane. The downstream formulation process for lyophilized product includes dissolution in water for injection, filling into Type I borosilicate glass vials under a restricted-access barrier system, and freeze-drying with shelf ramp from -40 °C to +25 °C at chamber pressure 0.1–0.3 mbar. Solution-injection forms are sterile-filtered and filled under nitrogen. Release standards include ICH Q3D elemental impurity risk assessment, USP <85> bacterial endotoxins, USP <787> and USP <788> for particulate matter, ICH Q3C for residual solvents, and 21 CFR 211.165 for finished-product release testing. Terminal product types are lyophilized powder for injection in single-dose vials and ready-to-use solution for injection in glass ampoules. Residual DPL clearance becomes mass-transfer-limited when the phase-cut temperature falls below 10 °C; amine-based buffers are avoided before extraction because they form soluble salts with the chiral auxiliary and reduce extraction efficiency.
Capsule-Grade Chiral β-Hydroxy Ketone Intermediates Produced by DPL-Catalyzed Direct Aldol Addition
Charging ratio records from pilot campaigns show DPL at 10–25 mol% relative to the aromatic aldehyde, with acetic acid at 5–10 mol% to accelerate enamine formation and reduce the induction period. The reaction is run at 0–35 °C for 18–48 h under a nitrogen blanket; the catalyst is not charged into bulk water because water above 5% v/v suppresses turnover. In the downstream process, a cylindrical reactor with bottom flush valve and retreat-curve impeller is used; after conversion reaches 85–95%, the mixture is diluted with methyl tert-butyl ether and washed with 1 M hydrochloric acid to protonate the pyrrolidine nitrogen and move spent catalyst into the aqueous phase. The organic layer is dried over anhydrous sodium sulfate, filtered, concentrated under vacuum at ≤40 °C, and crystallized by controlled addition of n-heptane at 0–5 °C. The resulting chiral β-hydroxy ketone is transformed to the final API and filled into hard gelatin or hypromellose capsules on a dosator-type capsule filler. Fill weight variation is held at ±5% of target; pin height is adjusted for API bulk density from 0.35 g/mL to 0.65 g/mL. Capsule shell moisture is controlled below 14% w/w during storage before filling. Release obligations include ICH Q7 for API manufacturing, ICH Q3C for residual solvents, USP <701> for capsule disintegration, USP <905> for content uniformity, and 21 CFR 211.165 for release testing. Terminal product types are immediate-release hard gelatin capsules and hypromellose vegetarian capsules. Catalyst turnover is depressed by ketone self-aldol products; process controls include aldehyde feed-rate limitation and periodic aqueous-phase removal to avoid salt precipitation. Addition of strong Lewis acids before aqueous workup is avoided because protonation of the chiral catalyst can reverse the aldol pathway.
When Fluid-Bed Top-Spray Granulation of Oral Granule APIs Demands Residual Solvent Reduction Below ICH Q3C Class 2 Limits
In fluid-bed processing, the DPL-derived API is incorporated at 2.5–10.0% w/w of dry granule mass, while the hydrophilic matrix contains mannitol 70–85% w/w, pregelatinized starch 8–12% w/w, and povidone K30 3–5% w/w dissolved in purified water. The downstream process uses a top-spray fluid bed with inlet air temperature 60–75 °C, product temperature 28–35 °C, atomizing air pressure 1.5–2.2 bar, and spray rate 15–35 g/min per kg of batch. Drying continues until loss on drying is ≤2.0% w/w; after dry milling, granules are classified to D50 150–350 µm according to USP <786>. Residual tetrahydrofuran arising from the API synthesis is determined by headspace gas chromatography per USP <467>, with reporting thresholds aligned to ICH Q3C. The finished granules are filled into single-dose sachets or high-density polyethylene bottles with desiccant. Release obligations include 21 CFR 211.165, USP <467>, USP <786>, and ICH Q3C. Terminal product types are single-dose oral granules, granules for oral suspension, and effervescent granules. When inlet air dew point exceeds 8 °C, granule particle size shifts coarse and disintegration slows; spray rates above 35 g/min per kg cause bed collapse and lump formation on the distributor plate. API residual moisture above 1.0% w/w may cause filter-bag sticking and kettle pressure fluctuation.
Direct compression of orally disintegrating tablets constitutes a distinct downstream path from fluid-bed granulation. The DPL-sourced API is blended at 3–10% w/w with mannitol 80–90% w/w, crospovidone 2–5% w/w, and sodium stearyl fumarate 0.5–1.5% w/w in a bin blender at 10–20 rpm for 15–25 min. The downstream process uses a rotary tablet press with main compaction force 8–15 kN and punch speed 30–60 rpm; tablet hardness is maintained at 30–60 N and friability below 1.0% w/w. In-process checks follow USP <905> for dosage-unit uniformity and USP <701> for disintegration; the target disintegration interval is 30–60 s in simulated saliva at 37 °C. Release standards include 21 CFR 211, ICH Q7 for the API, ICH Q3D for elemental impurities, and ICH Q3C for residual solvents. Terminal product types are oral disintegrating tablets and sublingual tablets. Compression room relative humidity above 40% RH increases sticking and edge chipping; pre-mix handling is restricted to ≤35% RH and ≤25 °C. If the API chiral purity falls below 99.0%, amorphous content increases and tablet crushing strength can drop; lubrication time above 25 min with sodium stearyl fumarate may reduce disintegration performance.
Competitive (R)-Diphenylprolinol Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable prices that fit your budget—flexible terms and customized quotes for every order.
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- (R)-Diphenylprolinol Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable is manufactured under an ISO 9001 quality system and complies with relevant regulatory requirements.
- COA, SDS/MSDS, and related certificates are available upon request. For certificate requests or inquiries, contact: sales10@sinochem-nanjing.com.
(R)-Diphenylprolinol Pharma Grade API is supplied as a white to off-white crystalline powder with the molecular formula C17H19NO and a molecular weight of 253.34 g/mol. The CAS registry number is 22348-32-9, and the stereochemical designation is (R)-α,α-diphenyl-2-pyrrolidinemethanol. The product is released under an ICH Q7-compliant API quality system and is designated for oral solid dosage forms and injectable preparations where the formulation dossier supports the intended use. Two physical model grades are specified: a standard grade with a particle-size ceiling of D90 ≤ 250 µm for tablet and capsule granulation, and a micronized grade with D90 ≤ 45 µm for injectable-suspension processing. The material is not supplied as a sterile product; downstream aseptic filtration or terminal sterilization is required for injectable finished-product release.
What Limits the Direct Compression Window for Tablet and Capsule Grades?
The direct compression window is controlled by three coupled factors: particle-size distribution, moisture uptake during blend hold time, and shear sensitivity of the low-melting free base. For standard tablet and capsule operations the product is screened through a 500 µm screen before blending. Bulk and tapped density are measured according to USP 616; the compressibility index and Hausner ratio are calculated from those measured values rather than assigned from supplier nominal data. A production-scale bin blender with 600 L working volume is commonly operated at 12 rpm for 20 min when the API is dry-blended with microcrystalline cellulose and croscarmellose sodium, but blend uniformity must be qualified for each batch size. Capsule filling with the standard grade is performed on a dosator or tamping-pin machine; low-dose capsules below 1 mg API fill weight typically require the micronized grade after granulation to meet content-uniformity acceptance criteria of 90%–110% label claim.
Published data on the Heckel yield pressure and tensile-strength profile of (R)-diphenylprolinol compacts are limited; formulation development should therefore use a compaction replicator with a flat-faced punch diameter of 11.28 mm before pilot-scale transfer. When dry granulation is selected, roller compaction with a roll force between 10 kN/cm and 20 kN/cm and a gap of 1.0–2.0 mm is a rational starting range; the resulting ribbons are milled through a 1.0 mm screen at low speed to avoid thermal softening. If wet granulation is used, povidone K30 is prepared as an aqueous 5% w/w binder solution and sprayed at a rate that maintains the bed temperature between 30 °C and 40 °C; granule moisture is dried to LOD ≤ 2.0% at 50 °C before lubrication. On a rotary tablet press operating above 35 rpm, punch-face sticking may occur if the compression zone temperature exceeds 35 °C; cooled punch surfaces or reduced turret speed are therefore used for direct compression trials.
Granule manufacturing for oral solid dosage forms proceeds by either high-shear top-spray granulation or fluid-bed granulation. The selected binder is prepared as an aqueous solution of povidone K30 in a 5% w/w concentration; binder spray rate is adjusted to maintain bed temperature between 30 °C and 40 °C. After drying, granules are milled through a 1.0 mm screen using a low-speed granulator operating below 1500 rpm to limit heat generation. Capsule filling of the dried granules is performed on a tamping-pin machine to a target fill weight derived from the granule bulk density and a target content uniformity of 95%–105% label claim.
Injectable formulation with the unmodified free base is limited by aqueous solubility, and the development of a solution dosage form requires salt formation or pH adjustment with a buffer system that maintains the molecule in a single ionized state. The micronized grade is dispersed in a preservative-free vehicle for suspension applications; particle-size distribution is re-evaluated after high-shear mixing and again after terminal autoclaving, because particle growth can occur. Sterile filtration through a 0.22 µm PVDF membrane is acceptable only when the API is fully dissolved; nylon membranes may show adsorptive losses and should be excluded from compatibility screening. For an injectable suspension, particulate matter is controlled by USP 788 and the endotoxin limit is calculated from the maximum adult clinical dose using USP 85, not from a universal API limit. Published data for the aqueous solubility and injection-site compatibility of this specific free-base configuration are limited.
Thermal Degradation and Moisture Sorption Remain the Primary Stability Constraints
Stability storage under ICH Q1A conditions is required for each physical grade. A standard protocol includes 40 °C / 75% RH for 6 months in open dish and in immediate packaging, and 25 °C / 60% RH for long-term evaluation. The product should be stored in double low-density polyethylene bags inside a sealed fiber drum, protected from light. Moisture sorption should be measured by dynamic vapor sorption; if the mass gain exceeds 0.5% at 60% RH, drying before processing may be required. Chiral inversion under accelerated conditions must be excluded because the (R)-enantiomer can be converted to the (S)-enantiomer under specific acid- or base-catalyzed conditions; the chiral purity method must therefore be stability-indicating for the opposite enantiomer. Differential scanning calorimetry and thermogravimetric analysis are performed at 10 K/min to detect melting onset, polymorph transitions, and desolvation. If a desolvation endotherm is detected below 100 °C, the material is not suitable for autoclave sterilization.
Representative release specifications for both physical grades are summarized below. These values are aligned with ICH Q6A for new drug substance specifications and are not a substitute for a regulatory dossier.
| Parameter | Test method | Control |
|---|---|---|
| Appearance | Visual examination, Ph. Eur. 2.2.1 | White to off-white crystalline powder |
| Infrared identification | Ph. Eur. 2.2.24 | Conforms to qualified reference standard |
| Specific optical rotation | Ph. Eur. 2.2.7, methanol, c = 1 | −58° to −63° |
| Chiral purity | Validated chiral HPLC | (S)-enantiomer ≤ 0.5% |
| Assay (HPLC) | Ph. Eur. 2.2.46 | 98.0%–102.0% on dried basis |
| Water content | Karl Fischer, Ph. Eur. 2.5.12 | Oral grade ≤ 1.0%; injectable grade ≤ 0.5% |
| Residue on ignition | Ph. Eur. 2.4.14 | ≤ 0.1% |
| Residual solvents | Headspace GC, Ph. Eur. 2.4.24 | ICH Q3C Class 2 and Class 3 solvents within limits |
| Elemental impurities | ICP-MS, USP 233 | ICH Q3D Option 1 limits for oral and injectable routes |
| Particle size | Laser diffraction, Ph. Eur. 2.9.31 | Standard D90 ≤ 250 µm; micronized D90 ≤ 45 µm |
| Bulk/tapped density | USP 616 | Report value |
| Microbial enumeration | USP 61 and 62 | Oral grade TAMC ≤ 103 CFU/g; TYMC ≤ 102 CFU/g |
| Bacterial endotoxins | USP 85 | Injectable grade limit calculated from clinical dose; API not supplied sterile |
When a Racemate or Opposite Enantiomer Is Present in Direct-Dosage Manufacture
The (S)-enantiomer and the racemate are not interchangeable with the (R)-enantiomer in a single-enantiomer pharmaceutical application. The (S)-enantiomer has the same molecular weight and formula but produces the opposite sign of optical rotation; it is controlled as a chiral impurity in the (R)-product. The racemate is a different crystalline entity and may have a different melting range and dissolution behavior than the pure enantiomer. Published commercial data on the comparative compaction and powder-flow behavior of the isolated enantiomer pair is limited, and a formulation developed with the racemate cannot be considered representative of the (R)-enantiomer without repeating content-uniformity and dissolution studies.
| Attribute | (R)-Diphenylprolinol | (S)-Diphenylprolinol | Racemic diphenylprolinol |
|---|---|---|---|
| Molecular weight | 253.34 g/mol | 253.34 g/mol | 253.34 g/mol |
| Specific optical rotation | Negative, approximately −58° to −63° in methanol at c = 1 | Positive, same magnitude as (R)-enantiomer | 0°, not chiral resolved |
| Chiral specification | (S)-enantiomer ≤ 0.5% | (R)-enantiomer ≤ 0.5% | Not applicable as a single enantiomer |
| Solid-state identity | Chiral crystalline form; polymorph must be controlled | Chiral crystalline form; may display different solid-state packing | Distinct racemic crystal or conglomerate; thermal behavior may differ |
| Dosage-form relevance | Pharma grade API for oral and injectable dosage forms | Mainly used as chiral reference or synthetic counterpart | Used for method qualification and impurity-marker studies |
| Regulatory interoperability | Single enantiomer specification required | Not interchangeable with (R)-API | Not interchangeable with (R)-API |
When developing a tablet or capsule with the (R)-enantiomer, traces of the (S)-enantiomer and the racemate must not be introduced through raw-material blend transfer or shared equipment. Cleaning validation swab limits should be calculated from toxicological or pharmacopeial limits for the opposite enantiomer and reported as a proportion of the maximum daily dose. Technical-grade or reagent-grade material differs from the pharma grade in that it may lack controlled chiral purity, ICH Q3D elemental-impurity data, and the GMP audit trail required under 21 CFR Part 210 and 211.
Analytical Method Validation and Reference-Standard Qualification
The product is not listed in a USP monograph; therefore, the release methods are validated under ICH Q2(R1) and qualified against a characterized in-house reference standard. Chiral HPLC uses an amylose-based chiral stationary phase with a hexane/alcohol mobile phase and UV detection at 220 nm; detection-limit solutions for the (S)-enantiomer are prepared at 0.05% relative concentration to confirm the method is suitable for the specified chiral-impurity limit. System suitability requires resolution between (R)- and (S)-enantiomers of at least 2.0 and relative standard deviation of the standard area below 2.0% across 6 injections.
Gas-chromatographic headspace analysis is calibrated for methanol, ethanol, dichloromethane, and toluene using reference solutions at 50% and 100% of the ICH Q3C limit. Inductively coupled plasma–mass spectrometry sample preparation uses closed-vessel microwave digestion with nitric acid and hydrogen peroxide; the method is validated for recovery between 70% and 150% over the range of the ICH Q3D permitted daily exposure. Particle-size method transfer from the supplier to the formulation site should include comparison of the obscuration range and dispersive air pressure used in dry laser diffraction, because the micronized grade is susceptible to agglomeration.
The API is shipped with batch-specific certificates of analysis, stability data where available, and a material safety data sheet. The retest period is assigned from long-term stability data, not from a default value. Any change in particle-size reduction, milling equipment, or solvent system in the final crystallization must trigger revalidation of the chiral purity and residue-on-ignition methods.
