Coprecipitated Amorphous Dispersions as Drug Substance: Opportunities and Challenges

Background: Enabling formulations have been implemented by the pharmaceutical industry as an effective tool for keeping Active Pharmaceutical Ingredient (API) in an amorphous state. Upon dosing in the amorphous state, many drugs which fail to demonstrate bioactivity due to the limited solubility and bioavailability of their crystalline form become bioavailable. Purpose: The analytical techniques use today for crystallinity detection are challenged by the sensitivity and robustness needed to achieve a 5% quantitation limit in low dose drug products. Our laboratory has developed a novel procedure capable of meeting this sensitivity and selectivity requirement. This is achieved by exploiting the differences in kinetic solubility of the formulated amorphous and free crystalline forms of API currently being used in dosage form platforms. Methods: Representative amorphous drug formulations were prepared and spiked with varying levels of crystalline drug substances to evaluate the selectivity and recovery of the crystalline drug substance from the product formulation. Kinetic solubility testing using a (i) Particle wetting phase, (ii) Particle suspending/erosion phase, (iii) Sampling time point and (iv) A total recovery determination for the drug substance. Results: The method selectively and quantitatively distinguishes crystalline drug substance from amorphous drug substance for samples spiked from 2.5% to 10% of the nominal label concentration of the API in the dosage form matrix. Conclusion: The kinetic solubility approach reported here achieves sensitive crystallinity quantitation for low drug level amorphous drug formulations at levels not yet achieved by complimentary analytical techniques.

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Investigation and Characterization of New Impurity in Clorsulon Drug Substance

Current Pharmaceutical Analysis ◽

10.2174/1573412913666170526160915 ◽

2018 ◽

Vol 14 (4) ◽

pp. 360-366

Author(s):

Natarajan Sivanandham ◽

Kempegowda Bommanadoddi Kempegowda

Keyword(s):

Drug Substance

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Validated chiral liquid chromatographic method for the enantiomeric separation of Tenofovir Disoproxil drug substance and its dosage forms

International Journal of Pharma and Bio Sciences ◽

10.22376/ijpbs.2019.10.4.p76-84 ◽

2019 ◽

Vol 10 (4) ◽

Author(s):

TUMMALA VIVEK ◽

BASAVAIAH K. ◽

B.M. RAO DR.

Keyword(s):

Chromatographic Method ◽

Enantiomeric Separation ◽

Dosage Forms ◽

Drug Substance ◽

Liquid Chromatographic Method ◽

Liquid Chromatographic

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Disulfiram Determination by Proton Magnetic Resonance Spectroscopy and by Colorimetry

Journal of AOAC INTERNATIONAL ◽

10.1093/jaoac/56.1.124 ◽

1973 ◽

Vol 56 (1) ◽

pp. 124-127 ◽

Cited By ~ 1

Author(s):

Eric B Sheinin ◽

Walter R Benson ◽

Myron M Smith

Keyword(s):

Magnetic Resonance ◽

Magnetic Resonance Spectroscopy ◽

Proton Magnetic Resonance ◽

Proton Magnetic Resonance Spectroscopy ◽

Colorimetric Method ◽

Drug Substance ◽

Resonance Spectroscopy ◽

Pmr Spectroscopy ◽

Label Claim ◽

Tablet Excipients

Abstract Disulfiram was determined in disulfiram drug substance and tablets by proton magnetic resonance (PMR) spectroscopy at the 100–480 mg level and by a colorimetric technique involving cuprous iodide at the 50 mg level. The tablet excipients do not interfere in the analysis. The average result for disulfiram in a tablet composite was 100.8±1.4% of label claim by PMR and 100.7±0.4% by the colorimetric method.

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Development of trace analysis for alkyl methanesulfonates in the delgocitinib drug substance using GC-FID and liquid–liquid extraction with ionic liquid

Open Chemistry ◽

10.1515/chem-2020-0093 ◽

2020 ◽

Vol 18 (1) ◽

pp. 1020-1029

Author(s):

Shinkichi Nomura ◽

Yoshiharu Ito ◽

Shigehiko Takegami ◽

Tatsuya Kitade

Keyword(s):

Ionic Liquid ◽

Trace Analysis ◽

Direct Injection ◽

Liquid Extraction ◽

Drug Substance ◽

Flame Ionization ◽

Liquid Liquid Extraction ◽

Accuracy And Precision ◽

Sensitivity And Selectivity ◽

Chloride Water

AbstractAlkyl methanesulfonates are genotoxic impurities that should be limited to an intake of not more than 1.5 µg/day, as regulated by the International Council for Harmonization guideline M7. We herein report a trace analysis of methyl methanesulfonate (MMS), ethyl methanesulfonate (EMS), and isopropyl methanesulfonate (IPMS) in the delgocitinib drug substance using liquid–liquid extraction, with an ionic liquid as the sample-solving medium, and direct injection gas chromatography detected with a flame-ionization detector. The proposed method takes advantage of the fine solubility of ionic liquids toward the drug substance, the good extraction efficiency of alkyl methanesulfonates in liquid–liquid extraction using the Chem Elut cartridge with low-polar organic solvents, and the ability of alkyl methanesulfonates to concentrate in minimum amounts of organic solvent, resulting in excellent sensitivity and selectivity. Specifically, for the preparation of the sample solution, a mixture of 1-butyl-3-methylimidazolium chloride, water, and acetonitrile was used as the sample-solving media, extracted with diethyl ether, and the eluent was concentrated to 1 mL. The method showed good linearity, accuracy, and precision from 1 to 5 ppm, and the limits of detection of MMS, EMS, and IPMS were 0.1, 0.05, and 0.05 ppm, respectively.

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