Drug Raw Materials Research Articles

Quantitation of amorphicity by microcalorimetry

The amorphous state of solids is characterized by a higher chemical and physical reactivity and a hygroscopic behaviour. Furthermore processing of amorphous powders is often difficult, because of the instability. Fast crystallizations, precipitations and milling favour the formation of the amorphous state. Galenical processes like granulation, drying, lyophilization, mixing, may also induce amorphous regions in the drug products. X-ray diffraction techniques can be used for the determination of the amorphicity of drug raw materials or drug products. Unfortunately, 10% is the detection limit, which in normal cases can be attained. Amorphous substances undergo an exothermic crystallization at temperatures above the glass transition point. Water which is a plasticizer decreases the temperature of the glass transition point, allowing the crystallization to occur at lower temperatures. The crystallization energy is measure of by microcalorimetry. Examples show the influence of the choice of the experimental conditions, especially the influence of the amorphicity on the kinetic of the reaction. Critical steps are discussed for three different drug substances. Limits of detection in the magnitude of 1 % are possible using microcalorimetry.

Liquid Chromatographic Determination of Tolrestat and Related Compounds in Raw Materials

Abstract A liquid chromatographic method was developed for the determination of tolrestat and 7 related compounds. The lower limit of quantitation of the related compounds in the presence of the drug was <0.05%. The coefficient of variation on the assay of drug raw material analyzed on 5 different days was 0.75%. Total impurities found in 2 samples of tolrestat from different sources were 0.12 and 0.54%, respectively. The method was validated by a second laboratory.

Liquid Chromatographic Methods for Fluoxetine Hydrochloride, Its meta Isomer, and Related Compounds in Raw Materials

Abstract Liquid chromatographic (LC) methods were developed for assay of fluoxetine hydrochloride, its meta isomer, and 12 related compounds in drug raw materials. The method for assay and determination of the meta isomer requires an Exsil ODS-B column; a mobile phase consisting of tetrahydrofuran, acetonitrile, and buffer; a flow rate of 1 mL/min; and detection at 214 nm. The method for related compounds specifies a Spherisorb nitrile column; a mobile phase consisting of tetrahydrofuran, acetonitrile, and buffer; a flow rate of 1 mL/min; and detection at 214 nm. The limits of quantitation in the presence of the drug are 0.1% for the meta isomer and 0.05% or less for the related compounds. Assay precision was less than 1.0% on triplicate weighings. Drug contents of 4 raw material samples were between 98.8 and 100.1%. Impurity levels in the 4 samples ranged from 0.14 to 0.45%. In addition, one sample contained ca 0.13% of the meta isomer. A second analyst, using columns from different suppliers, obtained similar results.

Liquid Chromatographic Determination of Amiodarone Hydrochloride and Related Compounds in Raw Materials and Tablets

Abstract A liquid chromatographic method for the determination of amiodarone hydrochloride and 10 related compounds in drug raw material and for assay of drug in tablets was developed. The method specifies a 3 jxm Hypersil nitrile column (150 × 4.6 mm), a mobile phase of 1 + 1 acetonitrile–ammonium acetate buffer (0.1 M adjusted to pH 6.0 with 0.1 M acetic acid), a flow rate of 1 mL/min, and detection at 240 nm. The lower limit of quantitation of the related compounds is 0.02% or less. Drug contents in 2 raw material samples were 100.1 and 99.9% and ranged from 98.2 to 99.4% in 3 tablet formulations. Impurity levels in 2 samples of raw material from different manufacturers were ca 0.4%. The presence of 3 of the known related compounds in these samples was confirmed by liquid chromatographymass spectrometry. The method applied to raw materials was evaluated by a second laboratory and found to be satisfactory.

Liquid Chromatographic Methods for Determination of Trazodone and Related Compounds in Drug Raw Materials

Abstract Liquid chromatographic methods for the determination of trazodone and 10 related compounds are described. An octylsilane column was used with a mobile phase of tetrahydrofuran–methanol–acetonitrile–0.5% trifluoroacetic acid (6 + 2 + 6 + 27) and detection at 248 nm. Minimum quantifiable amounts of the related compounds were less than 0.05% based on coefficients of variation of less than 10%. Total impurities in 5 raw drug materials were less than 1 %.

HPLC and NMR methods for the quantitation of the (R)‐enantiomer in (−)‐(S)‐timolol maleate drug raw materials

AbstractHPLC and 1H‐NMR methods for the quantitation of the (R)‐enantiomer in (−)‐(S)‐timolol maleate were developed and validated. The HPLC method requires a 25 cm × 4.6 mm 5 μm Chiracel OD‐H (cellulose tris‐3,5‐dimethylphenylcarbamate) column, a mobile phase of 0.2% (v/v) diethylamine and 4% (v/v) isopropanol in hexane at a flow rate of 1 ml/min and UV detection at 297 nm. A system suitability test was devised to verify the separation of the (R)‐ and (S)‐enantiomers of timolol from other drug‐related impurities. The NMR method requires the use of a high‐field NMR spectrometer (>360 MHz) and a chiral solvating agent, (−)‐(R)‐2,2,2‐trifluoro‐1‐(9‐anthrylethanol) (R‐TFAE). The limits of quantitation were 0.05% and 0.2% (m/m) for HPLC and NMR, respectively. The methods were applied to the determination of the (R)‐enantiomer in eight lots of raw material. The results for the two methods were in very good agreement, with results ranging from 0.1 to 4.1% (m/m) by HPLC and none detected to 4.3% (m/m) by NMR. The USP method for specific rotation was found to be unsuitable for detecting the presence of low levels of the (R)‐enantiomer in (−)‐(S)‐timolol maleate. © 1994 Wiley‐Liss, Inc.

Liquid Chromatographic Determination of Glyburide (Glibenclamide) and Its Related Compounds in Raw Materials

Abstract A liquid chromatographic method has been developed for the determination of glyburide and 3 known related compounds in drug raw materials. The lower limit of quantitation of the related compounds is about 0.02%. Evaluation of 9 drug raw materials revealed total impurities ranging from 0.17 to 0.65%. The relative standard deviation of the assay method is <1%.

Liquid Chromatographic Determination of Alprazolam and Related Impurities in the Drug Substance

Abstract A liquid chromatographic method was developed for the determination of alprazolam and 5 known related compounds in drug raw materials. The method is based on a 3 µm cyano column (100 x 4.6 mm), a mobile phase of 0.01% phosphoric acidacetonitrile- methanol (6 + 3 +1), a flow rate of 1.5 mL/min, and detection at 230 nm. The method resolves the related compounds from the drug and from each other. The limit of quantitation for the impurities in drug raw material is less than 0.1%. Impurity levels in 4 drug raw materials were between 0.01 and 0.41 %. The corresponding mean assay values ranged from 98.3 to 100.6%.

Gas Chromatographic Methods for Doxepin Isomers, Related Compounds, and Organic Volatile Impurities in Raw Materials and Doxepin Isomers in Capsules

Abstract Gas chromatographic methods have been developed for the determination of doxepin as the sum of the resolved E and Z isomers, 4 doxepin-related compounds, and organic volatile impurities in drug raw material. Minimum quantifiable amounts of the related compounds in raw materials are less than 0.05%. A method for assay of doxepin, as the total of the E and Z isomers, in capsules was also developed; relative standard deviation is less than 1% for the drug assay. Eleven raw material and 18 capsule samples were examined. No drug-related compounds or U.S. Pharmacopeia- or European Pharmacopeia-limited organic volatile impurities were detected in any of the samples.

Methods for Assay and Related Substances in Nitrendipine Raw Materials

Abstract A liquid chromatographic method has been developed for the determination of nitrendipine and related compounds in drug raw material. The method resolves the available related compounds from the drug and each other. The limit of quantitation for the related compounds is about 0.05%.

Methods for Assay, Related Substances, and Organic Volatile Impurities in Triazolam Raw Materials and Formulations

Abstract Liquid chromatographic methods have been developed for determination of triazolam and related compounds in drug raw materials and tablets. The methods resolve 9 available related compounds from the drug with quantitation limits of 0.1 % or less. Eight raw materials and 16 formulations were examined for related compounds. Total impurities in raw materials ranged up to 0.6% and up to 1% in formulations, not including a compound in some tablets that is believed to be excipient related. Assay values were between 99.9 and 101.3% for raw materials and between 89.4 and 105.5% for tablets. A gas chromatographic method was developed for organic volatile Impurities in drug raw materials. The major solvents found were methyl ethyl ketone (100-750 ppm), ethyl acetate (510 ppm), and n-propanol (80-300 ppm), with a trace of benzene (<30 ppm) in several samples.

Liquid Chromatographic Method for Selegiline Hydrochloride and Related Compounds in Raw Materials and Tablets

Abstract A liquid chromatographic method has been developed for determination of selegiline hydrochloride and related substances in drug raw material and tablet formulations. The method resolves 3 known related compounds from the drug with a limit of quantitation of less than 0.05%. Drug raw material and tablet samples contained ca 0.2 and 0.6% impurities, respectively. These included some related compounds, the identities of which were confirmed by gas chromatography with a Fourier transform Infrared detector.

Validation of an HPLC Method for Nifedipine and its Related Substances in Raw Materials

Abstract The USP HPLC method for related compounds in nifedipine has been modified to improve resolution and sensitivity. the modified method uses a Novopak' CI8 column with a mobile phase consisting of 48% methanol in water. This method has been validated for the determination of drug and related compounds in drug raw materials; it has been shown to resolve at least seven known related compounds from the drug, with quantitation limits ranging from 0.01 to 0.10%. Total impurities in 15 samples of drug raw material were between 0.02 and 0.85%. the drug content of these samples ranged between 97.9 and 102.0%.

Quantitative determination of ajmaline in drug raw material

Quantitative determination of ajmaline in drug raw material

High-performance liquid chromatographic method for the assay of verapamil hydrochloride and related compounds in raw material

A modification of the USP HPLC method [ United States Pharmacopeia XXII, pp. 1444-1446] for the assay of the purity of verapamil hydrochloride has been evaluated for the determination of the drug content and related compounds in drug raw material. The method enables the resolution of 16 related compounds from the parent drug and, in most cases, from each other. The minimum quantifiable amount for most related compounds is less than 0.05%. Six drug raw material samples are analysed and the total impurities found to be 0.3% or less. All drug assay values were within the USP recommended limits of 99.0-100.5%.

Validation of Methods for the Assay of Flurbiprofen and Flurbiprofen Sodium, Related Compounds and Volatile Impurities in Raw Materials and Tablets

A high performance liquid chromatographic method has been developed for the assay of flurbiprofen, or flurbiprofen sodium and related compounds in drug raw materials and tablets. A phenyl column with a mobile phase of acetonitrile: 1.0% acetic acid (60:40) provide for the resolution of twenty-one related compounds from the drug. Minimum detectable levels of the related compounds are 0.01% and minimum quantifiable levels are 0.1% or less. Total impurity levels in seven raw materials ranged from 0.0 to 0.6%. One impurity, 2-(4-biphenylyl) propionic acid, is present in most samples at about 0.3%. A gas chromatographic method was developed for organic volatile impurities

A one year controlled release implant for the luteinizing hormone releasing hormone superagonist RS-49947. I. Implant characterization and analysis of in vitro results

RS-49947 ([ d-Nal 6,aza-Gly 10]-luteinizing hormone releasing hormone)-silicone elastomer implants exhibit one year of therapeutic drug release in the target species, the canine [1]. Twentyone batches of these nonerodible porous matrix implants were studied by in vitro methodology to assess the effects of drug loading level, gamma irradiation dose, drug particle size and implant size on drug release. In vitro release data as a function of drug loading level are consistent with percolation theory [2–4], or modified percolation theory for small implant size [5]. The implants exhibit a percolation threshold [6–8] at ca. 30–35% of drug raw material. Simple geometric considerations are consistent with observed drug particle and implant size effects on in vitro release results. This model is consistent with an RS-49947 drug particle diameter in the implant of 100 μm. The drug raw material used to make these implants exhibits a unique morphology. Each drug powder particle is an agglomerate of sub-μm sized spheroidal primary particles. The sub-structure to each drug powder particle suggests that contacts between drug particles in the implant would occur on two size scales: (1) inter-particle contacts on a tens or hundreds of μm scale, and (2) intra-particle (primary particle) contacts on a sub-μm scale. Consistent in vitro release results are achieved without any control of overall gross drug particle size. Deagglomeration of RS-49947 drug raw material during the implant manufacturing process could explain the consistent implant performance.

A one year controlled release implant for the luteinizing hormone releasing hormone superagonist RS-49947. II. Clinical performance results

A small macroporous nonerodible matrix implant supplying therapeutic levels of the decapeptide drug RS-49947 ([ d-Nal(2) 6,aza-Gly 10]-luteinizing hormone releasing hormone) for one year is described and analyzed. The implant is indicated for estrus or male sexual behavior suppression (reversible chemical castration), or for the treatment of sex hormone dependent diseases in the canine or feline. These small (55 mg) slab devices are implanted below the ventral surface skin of the animal through a small incision, and can be removed or replaced at the end of one year of therapy. The optimal system contains 41% of water soluble drug raw material (33.6% theoretical of RS-49947 free base) dispersed in Silastic 382 silicone elastomer. Plasma levels of drug and clinical performance parameters in the canine are presented for the optimal formulation and for formulations containing higher (44% drug solubles) and lower (39% drug solubles) percentages of drug raw material. Formulations containing 39% or 41% of drug raw material release in vivo by an unanticipated apparent zero order release mechanism. Comparison of clinical and in vitro data suggests that in vivo itmechanisms may control drug release rates from these systems. In vitro data for these implants are consistent with current knowledge of macroporous implants, while the in vivo data show anomalous drug release durations and profile shapes. Hypotheses for the differences between in vitro and in vivo drug release are presented. The drug raw material used to manufacture these implants exhibits a unique morphology, which may further complicate understanding of the in vivo release results. In vitro data for these systems give some insight into in vivo release, although the mechanisms of in vitro and in vivo drug release apparently differ.

Determination of Diclofenac Sodium and Related Compounds in Raw Materials and Formulations

A liquid chromatographic method has been developed for determination of drug and related compounds in diclofenac sodium raw material, slow-release, and enteric coated tablets. The method specifies a 5 microns octadecylsilane bonded phase column, a mobile phase of tetrahydrofuran-acetonitrile-buffer, pH 5 (1 + 4 + 8.3), and detection at 229 nm. The method resolves 10 known related compounds with limits of quantitation of 0.2% or less. Seventeen drug raw material samples were evaluated. Total impurity levels ranged from 0.1 to 0.9%. The method has also been used for determination of drug content in raw materials and formulations. Mean assay levels in drug raw materials ranged between 98.3% and 101.8%.

Liquid chromatographic methods for the determination of albuterol (salbutamol), albuterol sulphate and related compounds in drug raw materials, tablets and inhalers

Liquid chromatographic methods for the determination of albuterol (salbutamol), albuterol sulphate and related compounds in drug raw materials, tablets and inhalers are described. The methods resolve five known related compounds from the drug and, in the case of inhalers, several compounds not related to the drug. Two of these were identified as 2,6-di-t-butyl-4-methylphenol, a common antioxidant, and 2,2'-methylene bis(6-t-butyl-4-methylphenol). Related compounds are detectable at levels of about 0.03%. Eleven albuterol and 12 albuterol sulphate raw materials and eight tablet formulations were found to contain related compounds ranging from 0.03 to 0.54%, 0.09 to 0.50% and 0.32 to 0.95%, respectively. Non-drug compounds in three inhaler samples ranged from 4.6 to 12% of the drug delivered through the valve. Some of the non-drug compounds may be excipients.