Final Dosage Form Research Articles

Formulation and the Study of Finished Products used for Anginal Disease

Congestive heart failure is a type of disease which is mainly observed due to the improper supply of blood to the heart. In this disease patient feels severe pain in the chest and may cause serious illness. Sudden treatment is needed in this disease to prevent any fatality. Nitroglycerin is the choice of drug for this disease. This study prepares a dosage form that can deliver the drug at a fast rate like a sublingual tablet of nitroglycerin. Sublingual dosage form was manufactured by direct compression method. For the formulation, multiple excipients like super disintegrants, sweeteners and lubricants were used. The finished dosage form was evaluated for different quality parameters. Optimum formulation was compared with the marketed product and kept on the accelerated stability study. Results were observed as satisfactory and comparable with the marketed product.

Application of Twin-Screw Melt Granulation to Overcome the Poor Tabletability of a High Dose Drug.

Pharmaceutical tablet manufacturing has seen a paradigm shift toward continuous manufacturing and twin-screw granulation-based technologies have catalyzed this shift. Twin-screw granulator can simultaneously perform unit operations like mixing, granulation, and drying of the granules. The present study investigates the impact of polymer concentration and processing parameters of twin-screw melt granulation, on flow properties and compaction characteristics of a model drug having high dose and poor tabletability. Acetaminophen (AAP) and polyvinylpyrrolidone vinyl acetate (PVPVA) were used as a model drug (90-95% w/w) and polymeric binder (5-10%w/w), respectively, for the current study. Feed rate (~650-1150g/h), extruder screw speed (150-300rpm), and temperature (60-150°C) were used as processing variables. Results showed the reduction in particle size of drug in the extrudates (D90 of 15-25μm from ~80μm), irrespective of processing condition, while flow properties were a function of polymer concentration. Overall, good flowability of the products and their tablets with optimum tensile strength can be obtained through using high polymer concentration (i.e., 10% w/w), lower feed rate (~650g/h), lower extruder screw speed (150rpm), and higher processing temperatures (up to 120°C). The findings from the current study can be useful for continuous manufacturing of tablets of high dose drugs with minimal excipient loading in the final dosage form.

Predicting Spray Dried Dispersion Particle Size Via Machine Learning Regression Methods

Spray dried dispersion particle size is a critical quality attribute that impacts bioavailability and manufacturability of the spray drying process and final dosage form. Substantial experimentation has been required to relate formulation and process parameters to particle size with the results limited to a single active pharmaceutical ingredient (API). This is the first study that demonstrates prediction of particle size independent of API for a wide range of formulation and process parameters at pilot and commercial scale. Additionally we developed a strategy with formulation and target particle size as inputs to define a set of “first to try” process parameters. An ensemble machine learning model was created to predict dried particle size across pilot and production scale spray dryers, with prediction errors between −7.7% and 18.6% (25th/75th percentiles) for a hold-out evaluation set. Shapley additive explanations identified how changes in formulation and process parameters drove variations in model predictions of dried particle size and were found to be consistent with mechanistic understanding of the particle formation process. Additionally, an optimization strategy used the predictive model to determine initial estimates for process parameter values that best achieve a target particle size for a provided formulation. The optimization strategy was employed to estimate process parameters in the hold-out evaluation set and to illustrate selection of process parameters during scale-up. The results of this study illustrate how trained regression models can reduce the experimental effort required to create an in-silico design space for new molecules during early-stage process development and subsequent scale-up.

Chitosan and Sodium Alginate Implementation as Pharmaceutical Excipients in Multiple-Unit Particulate Systems

This study aimed to prepare and evaluate pellets containing acyclovir as a model drug. Pellets were prepared by the extrusion–spheronization process. Aqueous solutions of natural marine polymers (sodium alginate, chitosan) were compared to semi-synthetic hydroxypropyl methylcellulose (HPMC) in the role of binders. The study focused on the characterization of the pellet properties that are crucial for the formulation of the final dosage form, such as in multi-unit pellet system (MUPS) tablets or hard gelatin capsules filled with the pellets. Finally, the mentioned dosage forms were tested for drug dissolution. The morphology of pellets observed by scanning electron microscopy correlated with the shape evaluation performed by dynamic image analysis. Sodium alginate pellets exhibited the lowest value of sphericity (0.93), and many elongated rods and dumbbells were observed in this batch. Chitosan pellets had the highest value of sphericity (0.97) and were also less rough on the surface. The pellets maintained a constant surface geometry during the dissolution studies; they only reduced in size. The most significant reduction in size and weight was assessed after 2 h of dissolution testing. This fact was in line with the drug release from pellets in capsules or MUPS tablets, which was massive during the first hour, in both cases. The dissolution profiles of all of the batches were comparable.

Antigenic Components of Chemical Bivalent Cholera Vaccine, Methods of their Isolation and Control

The paper presents a review of the data on the methods of isolation and control of Vibrio cholerae antigens – cholerogen-anatoxin and O-antigens of Inaba and Ogawa – components of the oral bivalent chemical cholera vaccine produced by the RusRAPI “Microbe”, the only prophylactic drug against cholera registered in the territory of the Russian Federation. Currently, the vaccine is produced using the method of segregated manufacturing of cholerogenanatoxin and O-antigens Inaba and Ogawa with step-by-step control of their main properties, which ensures the production of a high-quality finished product. Ultrafiltration is an effective method for concentrating a semi-finished product, which helps to reduce losses and increases the yield of the final product. It remains promising to develop a method for gentle steril ization of O-antigens to maximize the preservation of specific activity. To control the specific activity of the antigenic components and the finished vaccine preparation, a complex of in vivo and in vitro methods is applied. However, the multi-stage process and duration, the use of several types of laboratory animals, as well as modern WHO requirements determine the need for the introduction of alternative in vitro control methods. The use of cell cultures as a replacement for the biological method appears prospective, and demonstrates a positive correlation with animal tests. To assess the activity of antigens, the use of an immunochemical method – dot-immunoassay with gold nanoparticles – is put forward, which will make it possible to harmonize the control method at all stages of the production process, as well as to determine the serovar specificity of Vibrio cholerae O-antigens. The development of molecular-genetic, microbiological, immunochemical methods is relevant for a more complete and comprehensive control of the main immunogens of industrial strains of cholera vibrio. The introduction of promising methods for obtaining antigens and monitoring their properties will allow for a more complete characterization of the component composition of the finished dosage form of the chemical cholera vaccine.

Development of the Composition and Technology of a Combined Drug Based on Microspheres with Doxorubicin Hydrochloride and Comenic Acid

Introduction. In recent decades, the role of X-ray endovascular methods has been progressing in the treatment of oncology. It became possible to perform embolization not only to stop bleeding from a tumor, but also for the purpose of targeted delivery of chemotherapy drugs. However, of particular interest is the development of new combined drugs that combine cytostatic action, embolization of blood vessels that feed the tumor, and analgesia. Aim. The aim of the study is to develop the composition and technology of a combined drug for parenteral administration, including lyophilized polymer microspheres saturated with doxorubicin hydrochloride and an injection solution of comenic acid. Materials and methods. The study of the sorption of comenic acid by polymeric microspheres was carried out using the HPLC method. Analysis of the appearance of polymeric microspheres and obtaining their photographic images was carried out by microscopy using a microscope with a digital camera. Results and discussion. The study made it possible to determine that comenic acid, unlike doxorubicin hydrochloride, is practically not sorbed by polymer microspheres, which justifies the expediency of including a solution of comenic acid in the composition of the finished dosage form in the form of a separate injection solution. It has been established that when obtaining lyophilized polymer microspheres saturated with doxorubicin hydrochloride, it is necessary to use water for injection as a solvent for doxorubicin hydrochloride lyophilisate. A combined medicinal product has been developed for use in the field of X-ray surgery, containing: a bottle with a lyophilizate of polymeric microspheres saturated with doxorubicin hydrochloride in a ratio of 1 : 2, intended for chemoembolization; an ampoule with a solution containing 20 mg/ml of comenic acid, intended for intravenous administration in order to relieve pain. Conclusion. As a result of the study, the possibility of sorption of comenic acid by polymeric microspheres was studied. A technology has been developed for obtaining polymeric microspheres saturated with doxorubicin hydrochloride. A combined drug intended for use in the field of X-ray surgery has been developed.

Evaluation of the antibacterial activity of the preparation benzydamine hydrochloride

Introduction. With an increase in the level of acquired antibiotic resistance of pathogens, treatment becomes more complicated and slows down, especially in infections associated with biofilms. There is a growing need for the development and use of new antibacterial drugs with specific antimicrobial activity.Aim. To study the antimicrobial action and the dynamics of the formation of resistance to benzydamine hydrochloride from a various infection agents. Materials and methods. To obtain biofilms, microorganisms were cultivated in flat-bottomed culture plates. Planktonic cells were obtained by suspending and reseeding single colonies of the daily culture into flat-bottomed culture plates. To determine the antimicrobial activity of the studied preparations, two-fold dilutions were prepared and added to the wells of the plate with a bacterial culture. The dynamics of the formation of resistance to benzydamine hydrochloride was studied by passaging the cultures in a liquid nutrient medium with increasing concentrations of the antiseptic by a twofold step. After 2–3 days of incubation from a test tube with the maximum concentration of the drug, in which bacterial growth was observed, the bacteria were transferred to new ones with higher concentrations of the drug.Results. It was shown that benzydamine hydrochloride showed a high level of activity against bacteria M. catarrhalis and yeast-like fungi C. albicans. A slightly lower activity of the drug was noted for bacteria of the species S. aureus and E. coli, however, within the limits of the therapeutic concentration of the drug in finished dosage forms. Benzydamine hydrochloride had a significantly higher level of antibacterial activity against pre-formed biofilms compared to drugs such as chlorhexidine and hexetidine. An analysis of the dynamics of the formation of resistance to the drug benzydamine hydrochloride in microorganisms of various species showed that the possibility of developing resistance to benzydamine hydrochloride is extremely small. The process of adaptation was observed only in E. coli. The studied strains of the species S. aureus, C. albicans, and M. catarrhalis did not acquire resistance to the test drug.Conclusion. Benzydamine hydrochloride can be effectively used against a wide range of pathogens of ENT infections, as it has been shown to have a significantly higher level of antibacterial activity against pre-formed biofilms, various types of bacteria and yeast-like fungi and an extremely low level of resistance compared to other antiseptic drugs.

International Regulatory Collaboration on the Analysis of Nitrosamines in Metformin-Containing Medicines

Recalls of some batches of metformin have occurred due to the detection of N-nitrosodimethylamine (NDMA) in amounts above the acceptable intake (AI) of 96 ng per day. Prior to the recalls, an international regulatory laboratory network had been monitoring drugs for nitrosamine impurities with each laboratory independently developing and validating multiple analytical procedures to detect and measure nitrosamines in metformin drugs used in their jurisdictions. Here, we provide an overview of the analysis of metformin active pharmaceutical ingredients (APIs) and drug products with 1090 samples (875 finished dosage forms (FDFs) and 215 API samples) tested beginning in November of 2019 through July of 2020. Samples were obtained internationally by a variety of approaches, including purchased, received from firms via information requests or selected by regional regulatory authorities (either at wholesalers or during GMP inspections). Only one nitrosamine (NDMA) was detected and was only present in some batches of metformin products. For API samples, 213 out of 215 lots tested had no measurable level of NDMA. For FDF samples tested, the number of batches with NDMA above the AI amount for patient safety was 17.8% (156/875). Based on these data, although the presence of NDMA was of concern, 82.2% of the samples of metformin drug products tested met quality and safety standards for patients. Regulatory agencies continue to collaborate extensively and work with marketing authorization holders to understand root causes of nitrosamine formation and agree on corrective actions to mitigate the presence of NDMA in future metformin batches.Graphical abstract

Investigation of Quantitative X-ray Microscopy for Assessment of API and Excipient Microstructure Evolution in Solid Dosage Processing.

Assessment and understanding of changes in particle size of active pharmaceutical ingredients (API) and excipients as a function of solid dosage form processing is an important but under-investigated area that can impact drug product quality. In this study, X-ray microscopy (XRM) was investigated as a method for determining the in situ particle size distribution of API agglomerates and an excipient at different processing stages in tablet manufacturing. An artificial intelligence (AI)-facilitated XRM image analysis tool was applied for quantitative analysis of thousands of individual particles, both of the API and the major filler component of the formulation, microcrystalline cellulose (MCC). Domain size distributions for API and MCC were generated along with the calculation of the porosity of each respective component. The API domain size distributions correlated with laser diffraction measurements and sieve analysis of the API, formulation blend, and granulation. The XRM analysis demonstrated that attrition of the API agglomerates occurred secondary to the granulation stage. These results were corroborated by particle size distribution and sieve potency data which showed generation of an API fines fraction. Additionally, changes in the XRM-calculated size distribution of MCC particles in subsequent processing steps were rationalized based on the known plastic deformation mechanism of MCC. The XRM data indicated that size distribution of the primary MCC particles, which make up the larger functional MCC agglomerates, is conserved across the stages of processing. The results indicate that XRM can be successfully applied as a direct, non-invasive method to track API and excipient particle properties and microstructure for in-process control samples and in the final solid dosage form. The XRM and AI image analysis methodology provides a data-rich way to interrogate the impact of processing stresses on API and excipients for enhanced process understanding and utilization for Quality by Design (QbD).

Development and validation of liquid chromatography method for determination of Ibrutinib in finished dosage forms using quality by design approach

AbstractA simple, precise, linear, robust, accurate, and stability‐indicating liquid chromatography method was developed and validated to determine Ibrutinib in finished solid dosage forms by reversed‐phase high‐performance liquid chromatography/photodiode array detector. Separation was achieved using a Luna C18 150 mm × 4.6 mm × 3.0 μm with a suitable mobile phase. The mobile phase: A consists of a 10 mM phosphate buffer concentration and 1 mL triethylamine, adjusted to pH 5.6 with a diluted orthophosphoric acid solution and acetonitrile in the ratio of 95:5 v/v to enhance the results. Moreover, mobile phase ‐ B contains 85% of acetonitrile. The optimized chromatographic conditions such as flow rate 1.0 mL/min, injection volume 10 μL, column temperature 40°C, and wavelength 258 nm. The proposed method is significant because it was developed by the Quality by Design approach. All impurities were identified, such as degradation and placebo impurities without interference at principle peak retention time. After development, it has been validated as per current regulatory guidelines. Obtained recovery between 98 and 102% at 50–200% level; linearity found (r2) = 0.9999 from 20 to 200% level; precision results achieved <2.0% relative standard deviation; and the robustness study results are found satisfactory. It's beneficial.

Assessment of pharmaceutical powders flowability and comparative evaluation of lubricants on development of gastro retentive tablets: An application of powder flow tester

Lubricants have a small appearance but act as a giant frame in flow behavior during dosage form preparation. In the present study, different lubricants were evaluated and compared. Both traditional and advanced techniques were used to evaluate raw materials and prepared granules' flow properties. The powder was evaluated traditionally in terms of known and straight forward methods. Despite of that, the results like dissolution and content uniformity varied during the final dosage form preparation. Powder Flow Tester (PFT) was utilized to overcome these limitations and explore micromeretic properties. All the raw materials were found under the cohesive region in the flow function test except sodium bicarbonate. Agglomeration of powder into granules and the addition of lubricants improved the flow behavior. The hydrophilic sodium stearyl fumarate enhanced the nature of flow pattern and showed a synergistic impact on the evaluation of the final dosage form. It showed 35.6° hopper half-angle at 1.343 m outlet dimension-least value amongst all which specifies the flow pattern of granules in the hopper to die cavity at the time of manufacturing.

A Fundamental Study on Compression Properties and Strain Rate Sensitivity of Spray-Dried Amorphous Solid Dispersions

Amorphous solid dispersions (ASDs) are a proven method of improving the solubility and bioavailability of poorly soluble compounds. Immediate release tablets are frequently used as final dosage form for ASDs. Increasing tableting process throughput during clinical development requires using larger, faster tablet presses which subject materials to higher strain rate. Many pharmaceutical materials show strain rate sensitivity, i.e., yield pressure sensitivity to compression speed. Currently, there is only scattered information available in scientific literature on how ASDs behave under different tablet compression speeds. The purpose of this study was to examine spray-dried ASDs' sensitivity to strain rate under compression in a comprehensive study. We also investigated the drivers for such a strain sensitive behavior. A set of sample spray-dried powders, selected for their range of properties, were compressed using a simulated Korsch XL100 profile at 3 and 30 RPM and V-profile at 0.1 and 300mm/s on a Phoenix compaction simulator. The sample set included samples with varying API content (0-50% w/w), stabilizing polymer (HPMC, HPMC-AS, PVP-VA), particle size, and bulk densities, produced on spray driers from lab to commercial scale. We identified that all ASD samples showed plastic flow and deformation behavior and form robust compacts at slow compression speeds. At high speed, tablet defects occurred. The strain rate sensitivity observed in this study was comparable or slightly superior to that observed for microcrystalline cellulose, known to be a mildly strain rate-sensitive material. We showed that compression speed is a critical process parameter for ASD-containing tablets.

Nitrocellulose blister material as a source of N-nitrosamine contamination of pharmaceutical drug products

The recent focus of pharmaceutical regulatory authorities has been oriented towards the mitigation of carcinogenic N-nitrosamines in drug products and different sources of N-nitrosamines have been revealed. Within this work, the elucidation of a further source of N-nitrosamines in drug products is reported. A case was investigated where traces of N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) were detected in a finished dosage form, whereas they were not found in the bulk drug product. This led to an in-depth study of blister material as a potential source, wherein nitrocellulose primer in a lidding foil was identified as a risk factor. Nitrocellulose acts as a nitrosating agent for secondary amines, present in printing inks, forming N-nitrosamines in lidding foil. Their formation was confirmed by the addition of printing ink containing dimethylamine and diethylamine, or diethylamine alone, to lidding foil containing nitrocellulose primer. Their transfer to drug product during the blistering operation was demonstrated by solid-phase microextraction sampling of N-nitrosamine vapors on two commonly used types of pharmaceutical blistering machines, operating with plate sealing or roller sealing technology. Higher vapor amounts were detected on plate sealing equipment, where N-nitrosamine contamination was additionally confirmed in film-coated tablets and blister cavities of the finished dosage form.

Surveillance of Stability Under Different Stress Conditions in Desloratadine and Study of Degradation Kinetics.

A stability-indicating method (SIM) stipulates the testing of the drug product and drug substances under the stressed conditions that will imply a clear notion about the stress conditions that would affect the drug in its finished dosage form. Furthermore, manufactures can clearly define the state at which the drug is unstable and present its storage conditions. The present article deals with the stability testing and degradation kinetic studies of desloratadine (DL). The method of analysis was UV visible spectroscopy, which is a most convenient and reliable method for the analyst. A method was developed and validated according to the ICH Q2 guidelines along with the amendment in 2018 (ICH Q14). The study denotes that the drug is extremely unstable in the presence of dry heat and then follows the oxidative and basic degradations. The acidic, neutral, and photolysis did not show notable degradations. The chemical kinetic studies were carried out to more clearly understand the mechanism of degradation and to present the order of reaction, rate of reaction, and reaction half-time. The application of a spectrophotometric method in the development of a SIM and study of degradation kinetics is much handier and cost-effective.

Countries Manufacturing Pharmaceuticals for the US Market: A 10-Year Analysis of Public Data

Concerns about strategic supplies and quality have increased the scrutiny of the countries where US pharmaceuticals are made. To examine the locations of manufacturers of brand name, biological, and generic drugs over 10 years. This longitudinal descriptive study used publicly available data from US government Web sites, including the Food and Drug Administration (FDA) Drug Establishments list, FDA National Drug Code Directory, FDA Orange Book, FDA Purple Book, and the National Institutes of Health DailyMed Drug Labels. These data were collected from 2011 to 2020. Brand name drug manufacturing in the United States and Europe decreased from 89% in 2011 to 79% in 2020. Biological manufacturing in the United States decreased, while that in Western European countries increased; 100% of biological manufacturing was done in the United States or Europe in 2011 and decreased to 93% by 2020. Generic manufacturing in India increased from 21% to 51%, while US manufacturing decreased from 52% to 35% from 2011 to 2020. These analyses were limited to publicly available data, and the results could be affected by the accuracy and completeness of the data. Brand name drugs and biologicals are primarily made in the United States and Europe. Generic drugs are increasingly made in India, but the United States remains a major supplier. If the country of origin for pharmaceuticals is important, these findings support supply chain concerns for generic drugs. We recommend that product containers and official labeling prominently include the manufacturer and location for active pharmaceutical ingredients and finished dosage forms.

A Review on DMF Filing in EU, USA and Australia

Drug master file (DMF) is highly confidential information describing the aspect elements and error free information regarding API and finished dosage form. It consists of two parts. One is open part and another one is restricted part. Open part contains the information about the quality of drug product by the licence holder. Prohibited part which is Closed part which is protect the secret and unofficial information about manufacturing of product which is relived In front of respect regulatory authorities. When two or more persons involved in manufacturing of pharmaceutical. The drug master file contains overall information about product quality, maturing stability and purity of the medicaments. Drug master file gives the support to the IND (Investigational New Drug) application, ANDA (Abbreviated New Drug Application), NDA. Every country has its own drug filling format and content. The current observation is different countries drug master filing, content of drug master filing and format of the filing respect countries.

Performance and paroxetine stability in tablets manufactured by fused deposition modelling-based 3D printing.

The objective of this study was to develop a method for the preparation and characterization of paroxetine (PRX) tablets, obtained by coupling hot-melt extrusion and fused deposition modelling (FDM)-based three-dimensional printing (3DP) technology. The impact of the printing process parameters on the drug stability and on the tablets performance was assessed. Tablets were obtained by FDM of hot-melt extruded PRX-loaded filaments. Physicochemical, thermal, spectroscopic, diffractometric analysis and in-vitro dissolution tests of the intermediate products and the finished dosage forms were performed. The characterization of printed tablets evidenced mass and dimensions uniformity, and consistency of drug content and dissolution profile. The formation of amorphous solid dispersions and interaction of formulation components throughout the manufacturing process were demonstrated. Layer thickness, printing temperature, printing and travelling speeds, and infill were the most impacting process parameters on both the physicochemical properties and the in-vitro performance of the 3D-printed tablets. PRX tablets, meeting compendial limits, were manufactured by 3DP, envisaging their clinical use as individually designed dosage forms. The assessment of the impact of processing parameters on the printed tablets provided insights, which will ultimately allow streamlining of the 3D process set-up for quicker and easier production of patient-centric medicines.

Flux-Based Formulation Development\u2014A Proof of Concept Study

The work aimed to develop the Absorption Driven Drug Formulation (ADDF) concept, which is a new approach in formulation development to ensure that the drug product meets the expected absorption rate. The concept is built on the solubility-permeability interplay and the rate of supersaturation as the driving force of absorption. This paper presents the first case study using the ADDF concept where not only dissolution and solubility but also permeation of the drug is considered in every step of the formulation development. For that reason, parallel artificial membrane permeability assay (PAMPA) was used for excipient selection, small volume dissolution-permeation apparatus was used for testing amorphous solid dispersions (ASDs), and large volume dissolution-permeation tests were carried out to characterize the final dosage forms. The API-excipient interaction studies on PAMPA indicated differences when different fillers or surfactants were studied. These differences were then confirmed with small volume dissolution-permeation assays where the addition of Tween 80 to the ASDs decreased the flux dramatically. Also, the early indication of sorbitol’s advantage over mannitol by PAMPA has been confirmed in the investigation of the final dosage forms by large-scale dissolution-permeation tests. This difference between the fillers was observed in vivo as well. The presented case study demonstrated that the ADDF concept opens a new perspective in generic formulation development using fast and cost-effective flux-based screening methods in order to meet the bioequivalence criteria.Graphical

Synthesis of Rutin Derivatives to Enhance Lipid Solubility and Development of Topical Formulation with a Validated Analytical Method.

Rutin is available on the market as a topical formulation for the treatment of several conditions, such as internal bleeding, hemorrhoids, and varicose veins. However, these gels have low solubility and limited bioavailability due to their decreased lipid solubility. In this study, we aimed to synthesize potentially novel lipophilic rutin prodrugs. The suggested library of these rutin prodrugs includes changing the solubility profile to facilitate rutin transport across biological barriers, thereby improving drug delivery through topical application. Six rutin derivatives were synthesized based on the ester prodrug strategy. The synthesized compounds were formulated as topical ointments, and their permeability via Franz diffusion was measured. An ultraviolet (UV) analytical method was developed in our laboratories to quantify rutin derivatives both as raw materials and in final dosage forms. The analytical method was then validated. The results of Franz diffusion analyses showed that transdermal permeability increased by 10-fold for decaacetylated rutin compared to the other esterified rutins. A simple analytical method for the analysis of the formulated rutin ester was developed and validated. Moreover, the formulated ointment of decaacetylated rutin in our research laboratory was found to be stable under stability accelerated conditions. Synthesis of potentially more lipophilic compounds would yield novel rutin prodrugs suitable for topical formulation. This project provides a synthetic approach for many similar natural products. The research idea and strategy followed in this research project could be adapted by pharmaceutical and herbal establishments.

Development and validation of GC/MS method for determination of residual ethanol in Cannabis extract

Ethanol was found to be the most suitable solvent for optimal extraction of cannabinoids and terpenes from Cannabis herba. Since ethanol use can have a serious impact on human health, purification of pharmaceuticals after ethanol extraction is necessary. Ethanol belongs to Class 3 residual solvents and its concentration is limited to 5000 ppm (0.5%) in the final pharmaceutical dosage forms. Determination (quantification) of ethanol in the final extracts is crucial for the quality and safety of the product. A novel GC/MS method was developed and validated for the determination of residual ethanol in cannabis extracts. The developed method is rapid, specific, accurate and precise. The calibration curve was plotted between the obtained peak areas of ethanol (quantifier ion m/z=31) and its concentration at six different concentration levels. The response was linear over the range of 312.5 ppm – 10000 ppm (R2 =0.9995). The limit of quantification, the limit of detection, system repeatability, method precision and recovery are demonstrated to evaluate the performance of the analytical procedure. The recovery range for added ethanol was 88.44% to 108.57%. The achieved results confirmed that the proposed method is suitable for monitoring the concentration of ethanol in cannabis extracts. Keywords: residual ethanol, cannabis extracts, gas chromatography-mass spectrometry