On-demand continuous-flow production of pharmaceuticals in a compact, reconfigurable system.

Pharmaceutical manufacturing typically uses batch processing at multiple locations. Disadvantages of this approach include long production times and the potential for supply chain disruptions. As a preliminary demonstration of an alternative approach, we report here the continuous-flow synthesis and formulation of active pharmaceutical ingredients in a compact, reconfigurable manufacturing platform. Continuous end-to-end synthesis in the refrigerator-sized [1.0 meter (width) × 0.7 meter (length) × 1.8 meter (height)] system produces sufficient quantities per day to supply hundreds to thousands of oral or topical liquid doses of diphenhydramine hydrochloride, lidocaine hydrochloride, diazepam, and fluoxetine hydrochloride that meet U.S. Pharmacopeia standards. Underlying this flexible plug-and-play approach are substantial enabling advances in continuous-flow synthesis, complex multistep sequence telescoping, reaction engineering equipment, and real-time formulation.

Routine quality evaluation of benzodiazepine drugs to USP-NF specifications.

A GLC procedure was developed for the evaluation of diazepam, chlordiazepoxide, and flurazepam formulations to USP-NF specifications for drug content, content uniformity, impurities, and identity by retention times and peak areas. The polyimide column, instrument zone temperatures, gas flows, internal standard solution, extraction solvent, and auxiliary equipment were the same for each drug. No derivatization of the samples was required. The GLC assay values (mean of 10 individual dosage units) for diazepam and flurazepam products were in good agreement with the results obtained by the pharmacopeial composite assays. With chlordiazepoxide capsules, when the levels of the two pharmacopeial impurities determined by GLC were added to the GLC assay results (mean of 10), athe aggregate values were consistent wit the drug content results found by the nonspecific USP method. The procedure can be made sensitive to impurity levels of approximately 0.01% for 2-amino-5-chlorobenzophenone and to approximately 0.2% for 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one 4-oxide. With the equipment used, the estimated potential outputs in lots per working day for a complete quality profile (drug content, content uniformity, purity, and identity) were seven for chlordiazepoxide if no impurity test was required, five if such a test was required, eight for diazepam, and seven for flurazepam.

[Validation of an HPLC method for the analysis of decomposition products in injectable diazepam]. / Validácia HPLC metódy na analýzu rozkladných produktov diazepamu v injekciách diazepamu.

Diazepam is an important drug from the group of benzodiazepines, used in clinical practice for its sedative, hypnotic, anticonvulsive, myorelaxant, and primarily anxiolytic effects. Several kinetic studies have been published which show that diazepam is a drug sensitive to hydrolysis both in acid and alkaline media. The present study aimed to elaborate and validate a simple and rapid HPLC/UV method for simultaneous analysis of three decomposition products of diazepam in the presence of diazepam and to apply it also on the control of stability of the injectional solution of diazepam. The optimization of chromatographic conditions resulted in the use of the high-performance chromatographic column Zorbax ODS, the mobile phase represented by a mixture of acetonitrile/water in a ratio of 60/40 (w/w, %), flow rate 1.5 ml/min, and spectrophotometric detection at 242 nm. The elaborated method and the employed chromatographic system were successfully validated and they can be used in practice in the control of stability of injection solution of diazepam.

Simultaneous quantification of lopinavir and ritonavir in human plasma by high performance liquid chromatography coupled with UV detection.

High performance liquid chromatography was coupled with UV detection for simultaneous quantification of lopinavir (LPV) and ritonavir (RTV) in human plasma. This assay was sensitive, accurate and simple, and only used 200 µL of plasma sample. Samples were liquid-liquid extracted, and diazepam was used as an internal standard. The chromatographic separation was achieved on a C18 reversed-phase analytic column with a mobile phase of acetonitrile-sodium dihydrogen phosphate buffer (10 mmol L(-1), pH 4.80) (60:40, v/v). UV detection was conducted at 205 nm and the column oven was set at 40°C. Calibration curves were constructed between 0.5-20 µg mL(-1) for LPV and 0.05-5 µg mL(-1) for RTV. The relative standard deviations were 2.16%-3.20% for LPV and 2.12%-2.60% for RTV for intra-day analysis, and 2.34%-4.04% for LPV and 0.31%-4.94% for RTV for inter-day analysis. The accuracy was within 100%±10%. The mean extraction recoveries were 79.17%, 52.26% and 91.35% for RTV, LPV and diazepam, respectively. This method was successfully applied to human plasma samples from patients orally administered a salvage regimen of lopinavir-ritonavir tablets.

Colorimetric determination of diazepam in pharmaceutical preparations.

A colorimetric method is presented for the estimation of diazepam as the pure drug and in formulations. Diazepam is hydrolyzed with 6N HCl to 2-methylamino-5-chlorobenzophenone, which is extracted with chloroform to give a yellow solution whose absorbance is measured at 410 nm against a solvent blank. The color obeys Beer's law in the concentration range of 0-30 mug/ml. In 5 determinations, recovery was 99.0 +/- 1.9%. The method is applicable to pure diazepam and its formulations for oral and parenteral use. No interferences were observed from pyridoxine hydrochloride and commonly used preservatives, vehicles, and colors.

Stability of diazepam rectal gel in ambulance-like environments.

The objective of the present study was to evaluate the stability of diazepam rectal gel (Diastat) in various conditions of temperature and light exposure as might be found in ambulances. Three lots of Diastat (Xcel Pharmaceuticals, San Diego, CA) in various fill/syringe configurations were evaluated in controlled conditions of a freeze-thaw cycle, hard freeze (-30 degrees C for 72 hours), extreme light exposure (1,000 ft candles for 1 month), and long-term evaluation at either 30 degrees C or 40 degrees C. In the various configurations and tests, diazepam concentration always exceeded 95% of label, with no changes of note in excipients or physicochemical properties. The estimated shelf-life at 30 degrees C exceeds 48 months. Based on the results of the present study, the restocking frequency of Diastat in ambient storage conditions (eg, ambulances), could be up to 48 months in nonfreezing environments, as long as this does not exceed the labeled expiration date on the product.

Ketamine anesthesia with or without diazepam premedication for bone marrow punctures in children with acute lymphoblastic leukemia.

Ketamine is a drug widely used for analgesia and sedation of children for diagnostic and therapeutic procedures. The authors investigated in a randomized controlled clinical trial if diazepam premedication would have a beneficial effect on side effects related to ketamine anesthesia for bone marrow punctures (BMPs) in children with acute lymphoblastic leukemia (ALL). Sixteen children 4 years or older at the time of BMP were eligible. The first 2 BMPs after complete remission was obtained were studied. BMPs were performed under ketamine anesthesia (1.0-1.5 mg/kg i.v.), as usual. Patients were randomized to receive 1 h before the first BMP blinded, either diazepam or placebo orally and before the second BMP the other way round. Blood pressure, heart rate, and oxygen saturation were monitored, and patients were observed for signs of anxiety, pain, and other side effects. The patients were interviewed after each BMP and asked for their preference 1 week after the second BMP. Ketamine anesthesia appeared as safe and effective after diazepam premedication as after placebo premedication. From the interviews and questionnaires, it was clear that half of the children preferred diazepam premedication because of less awful dreaming and more gradual falling asleep and waking up. Diazepam premedication may be useful for selected children with ALL receiving ketamine anesthesia for BMPs.