Active Pharmaceutical Ingredient Content Research Articles

Development of a Near Infrared Spectroscopy method for the in-line quantitative bilastine drug determination during pharmaceutical powders blending

The Food and Drug Administration (FDA)’s guidelines and the Process Analytical Technology (PAT) approach conceptualize the idea of real time monitoring of a process, with the primary objective of improvement of quality and also of time and resources saving. New instruments are needed to perform an efficient PAT process control and Near Infrared Spectroscopy (NIRS), thanks to its rapid and drastic development of last years, could be a very good choice, in virtue of its high versatility, speed of analysis, non-destructiveness and absence of sample chemical treatment. This work was aimed to develop a NIR analytical method for bilastine assay in powder mixtures for direct compression. In particular, the use of NIR instrumentation should allow to control the bilastine concentration and the whole blending process, assuring the achievement of a homogeneous blend. The commercial tablet formulation of bilastine was particularly suitable for this purpose, due to its simple composition (four excipients) and direct compression manufacturing process. Calibration and validation set were prepared according to a Placket-Burman experimental design and acquired with a miniaturized NIR in-line instrument (MicroNIR by Viavi Solution Inc.). Chemometric was applied to optimize information extraction from spectra, by subjecting them to a Standard Normal Variate (SNV) and a Savitzky-Golay second derivative pre-treatment. This spectra pre-treatment, combined with the most suitable wavelength interval (resulted between 1087 and 1217 nm), enabled to obtain a Partial Least Square (PLS) model with a good predictive ability. The selected model, tried on laboratory and production batches, provided in both cases good assay predictions. Results were confirmed by traditional HPLC (High Performance Liquid Chromatography) API (Active Pharmaceutical Ingredient) content uniformity test on the final product.

The use of X-ray microtomography to investigate the microstructure of pharmaceutical tablets: Potentials and comparison to common physical methods

Within this study, tablets microstructure was investigated by X-ray microtomgraphy. The aim was to gain information about their microstructure, and thus, derive deeper interpretation of tablet properties (mechanical strength, component distribution) and qualified property functions. Challenges in image processing are discussed for the correct identification of solids and voids. Furthermore, XMT measurements are critically compared with complementary physical methods for characterizing active pharmaceutical ingredient (API) content and porosity and its distribution (mercury porosimetry, calculated tablet porosity, Focused Ion Beam-Scanning Electron Microscopy (FIB-SEM)). The derived porosity by XMT is generally lower than the calculated porosity based on geometrical data due to the resolution of the XMT in relation to the pore sizes in tablets. With rising compactions stress and API concentration, deviations between the actual and the calculated API decrease. XMT showed that API clusters are present for all tablets containing >1 wt% of ibuprofen. The 3D orientation of the components is assessable by deriving cord lengths along all dimensions of the tablets. An increasing compaction stress leads to rising cord lengths, showing higher connectivity of the respective material. Its lesser extent in the z-direction illustrates the anisotropy of the compaction process. Additionally, cracks in the fabric are identified in tablets without visible macroscopic damage. Finally, the application of XMT provides valuable structural insights if its limitations are taken into account and its strengths are fostered by advanced pre- and post-processing.

DEVELOPMENT AND VALIDATION OF STABILITY INDICATING RP-HPLC METHOD FOR THE SIMULTANEOUS ESTIMATION OF ETHINYL ESTRADIOL AND GESTODENE IN BULK AND PHARMACEUTICAL DOSAGE FORMS

Objective: The principal objective of this study is to develop and validate a simple, new, fast, selective, precise, and economic stability-indicating the RP-HPLC method for the simultaneous estimation of Ethinyl estradiol and Gestodene in a bulk and pharmaceutical dosage form.
 Methods: The present method was developed and validated on a Waters HPLC system using Phenomenex Gemini C18(250 mm × 4.6 mm i.d., 5 µm particle size) column and mobile phase composition of phosphate buffer: Acetonitrile (75:25 v/v) and the pH was adjusted to 3.6 using dilute orthophosphoric acid. The system was regulated at 1.0 ml/min flow rate at 237 nm UV detection.
 Results: The two drugs Ethinyl Estradiol and Gestodene, were eluted at 1.788 min and 3.475 min retention time, respectively. The analytical parameters such as accuracy, precision, linearity, LOD, LOQ, ruggedness, and robustness were used for validating the developed method according to International Conference on Harmonisation [ICH] guidelines. Linearity was exhibited over the concentration range of 10-50µg/ml and 25-125µg/ml for Ethinyl Estradiol and Gestodene, respectively. The method revealed the Limit of Detection and Quantitation values for Ethinyl Estradiol and Gestodene were 1.399µg/ml, 3.909µg/ml and 4.24µg/ml, 11.85µg/ml, respectively. The stress testing was carried out to give rise to degradation products by exposing the drugs to acid, alkali, thermal, oxidative, photolytic, and hydrolytic degradation. The obtained data showed that the content of Active pharmaceutical ingredients and the degradation products were successfully separated without any interference, which confirmed the stability-indicating nature of the developed method.
 Conclusion: The new, simple, rapid, selective, precise, and economic stability-indicating RP-HPLC method has been successfully developed and validated. It can be satisfactorily applied for the periodic laboratory quantitative estimation of Ethinyl Estradiol and Gestodene in formulations and active pharmaceutical ingredients.

A non-destructive NIR spectroscopic method combined with chemometry for simultaneous assay of paracetamol and caffeine in tablets

The use of near infrared (NIR) spectroscopy to predict the concentration of two active pharmaceutical ingredients (APIs), paracetamol and caffeine, in intact tablets, has been evaluated in this study. A partial least squares (PLS) regression model was developed using spectral data obtained on a calibration set consisting of 28 formulations containing 80, 90, 100, 110 and 120% of each API. Regression models were developed for each API, both using un-processed spectral data as well as after applying various spectra pre-processing methods. Cross-validation was used to select best calibration model. The selected model was validated in terms of precision, trueness, accuracy and linearity in a concentration ranging from 90 to 110% of the targeted APIs concentration. The applicability of the method was tested on tablets containing 300 mg paracetamol and 30 mg caffeine as targeted composition, and the API content predicted by the proposed NIR-chemometric method was not statistically different from the one obtained by HPLC method, used as a reference method. Thus, the method presented in the current paper is a step forward towards the implementation NIR as useful tool for monitoring the manufacturing process of fixed-dose combination tablets with paracetamol and caffeine.

API Content and Blend Uniformity Using Quantum Cascade Laser Spectroscopy Coupled with Multivariate Analysis.

The process analytical technology (PAT) initiative proposed by the US Food and Drug Administration (FDA) suggests innovative methods to better understand pharmaceutical processes. The development of analytical methods that quantify active pharmaceutical ingredients (APIs) in powders and tablets is fundamental to monitoring and controlling a drug product’s quality. Analytical methods based on vibrational spectroscopy do not require sample preparation and can be implemented during in-line manufacturing to maintain quality at each stage of operations. In this study, a mid-infrared (MIR) quantum cascade laser (QCL) spectroscopy-based protocol was performed to quantify ibuprofen in formulations of powder blends and tablets. Fourteen blends were prepared with varying concentrations from 0.0% to 21.0% (w/w) API. MIR laser spectra were collected in the spectral range of 990 to 1600 cm−1. Partial least squares (PLS) models were developed to correlate the intensities of vibrational signals with API concentrations in powder blends and tablets. PLS models were evaluated based on the following figures of merit: correlation coefficient (R2), root mean square error of calibration, root mean square error of prediction, root mean square error of cross-validation, and relative standard error of prediction. QCL assisted by multivariate analysis was demonstrated to be accurate and robust for analysis of the content and blend uniformity of pharmaceutical compounds.

Continuous downstream processing of milled electrospun fibers to tablets monitored by near-infrared and Raman spectroscopy

Electrospinning is a technology for manufacture of nano- and micro-sized fibers, which can enhance the dissolution properties of poorly water-soluble drugs. Tableting of electrospun fibers have been demonstrated in several studies, however, continuous manufacturing of tablets have not been realized yet. This research presents the first integrated continuous processing of milled drug-loaded electrospun materials to tablet form supplemented by process analytical tools for monitoring the active pharmaceutical ingredient (API) content. Electrospun fibers of an amorphous solid dispersion (ASD) of itraconazole and poly(vinylpyrrolidone-co-vinyl acetate) were produced using high speed electrospinning and afterwards milled. The milled fibers with an average fiber diameter of 1.6 ± 0.9 µm were continuously fed with a vibratory feeder into a twin-screw blender, which was integrated with a tableting machine to prepare tablets with ~ 10 kN compression force. The blend of fibers and excipients leaving the continuous blender was characterized with a bulk density of 0.43 g/cm3 and proved to be suitable for direct tablet compression. The ASD content, and thus the API content was determined in-line before tableting and at-line after tableting using near-infrared and Raman spectroscopy. The prepared tablets fulfilled the USP <905> content uniformity requirement based on the API content of ten randomly selected tablets. This work highlights that combining the advantages of electrospinning (e.g. less solvent, fast and gentle drying, low energy consumption, and amorphous products with high specific surface area) and the continuous technologies opens a new and effective way in the field of manufacturing of the poorly water-soluble APIs.

On-Site Pilot Testing of Hospital Wastewater Ozonation to Reduce Pharmaceutical Residues and Antibiotic-Resistant Bacteria.

Hospital sewage constitutes an important point source for antibiotics and antibiotic-resistant bacteria due to the high antibiotic use. Antibiotic resistance can develop and cause problems in sewage systems within hospitals and municipal wastewater treatment plants, thus, interventions to treat hospital sewage on-site are important. Ozonation has proven effective in treating relatively clean wastewater, but the effect on untreated wastewater is unclear. Therefore, we piloted implementation of ozonation to treat wastewater in a tertiary hospital in Uppsala, Sweden. We measured active pharmaceutical ingredients (APIs) using liquid chromatography-mass spectrometry and antibiotic-resistant Enterobacteriaceae using selective culturing pre- and post-ozonation. Comparing low (1 m3/h) and high (2 m3/h) flow, we obtained a ‘dose-dependent’ effect of API reduction (significant reduction of 12/29 APIs using low and 2/29 APIs using high flow, and a mean reduction of antibiotics of 41% using low vs. 6% using high flow, 25% vs. 6% for all APIs). There was no significant difference in the amount of antibiotic-resistant Enterobacteiaceae pre- and post-ozonation. Our results demonstrate that ozonation of untreated wastewater can reduce API content. However, due to the moderate API decrease and numerous practical challenges in the on-site setting, this specific ozonation system is not suitable to implement at full scale in our hospital.

Ecological Risk Assessment of Pharmaceuticals in the Transboundary Vecht River (Germany and The Netherlands).

Millions of people rely on active pharmaceutical ingredients (APIs) to prevent and cure a wide variety of illnesses in humans and animals, which has led to a steadily increasing consumption of APIs across the globe and concurrent releases of APIs into the environment. In the environment, APIs can have a detrimental impact on wildlife, particularly aquatic wildlife. Therefore, it is essential to assess their potential adverse effects to aquatic ecosystems. The European Water Framework Directive sets out that risk assessment should be performed at the catchment level, crossing borders where needed. The present study defines ecological risk profiles for surface water concentrations of 8 APIs (carbamazepine, ciprofloxacin, cyclophosphamide, diclofenac, erythromycin, 17α‐ethinylestradiol, metformin, and metoprolol) in the Vecht River, a transboundary river that crosses several German and Dutch regions. Ultimately, 3 main goals were achieved: 1) the geo‐referenced estimation of API concentrations in surface water using the geography‐referenced regional exposure assessment tool for European rivers; 2) the derivation of new predicted‐no‐effect concentrations for 7 of the studied APIs, of which 3 were lower than previously derived values; and 3) the creation of detailed spatially explicit ecological risk profiles of APIs under 2 distinct water flow scenarios. Under average flow conditions, carbamazepine, diclofenac, and 17α‐ethinylestradiol were systematically estimated to surpass safe ecological concentration thresholds in at least 68% of the catchment's water volume. This increases to 98% under dry summer conditions. Environ Toxicol Chem 2022;41:648–662. © 2021 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC

Miscibility and thermal properties of poly(vinylpyrrolidone-vinyl acetate)/lamivudine and tenofovir binary blends prepared by hot melt extrusion

Preparation of amorphous solid dispersions (ASD) by hot melt extrusion (HME) of poly(vinylpyrrolidone-vinyl acetate) (Kollidon) and the active pharmaceutical ingredients (API) Lamivudine (3TC) and Tenofovir Disoproxyl Fumarate (TDF) was investigated aiming to study their miscibility and thermal behavior. These two drugs are currently used as drugs in first line treatment of patients with Acquired Immunodeficiency Syndrome (AIDS). In order to predetermine parameters for extrusion and the maximum concentration of API to be used without any recrystallization, binary blends were first processed in the mixing chamber at 130°C using a roller type rotor at 10, 20 and 30 rpm for 7 min, giving rise to ASD of both API, at least up to 20 wt% of the drug. Both 3TC and TDF were then extruded individually with Kollidon in a single screw extruder. HME produced ASD with high concentration of both Kollidon/API combinations, being part of the API soluble in the polymer matrix. From HME, Kollidon/3TC forms ASD in concentration up to 50 wt%, but from 30 wt% 3TC, the ASD has no time stability, showing recrystallization in less than 5 months, while the Kollidon/TDF system forms ASD up to 30 wt% of TDF, but it has aging stability inferior to 4 months.

Impact of ciprofloxacin impurities on bacterial growth, antibiotic resistance development and content assays.

In addition to active pharmaceutical ingredient (API), antibiotics may contain small amounts of excipients and impurities and be prone to accumulation of degradation products. There has been limited work characterizing how these substances impact bacterial growth and antibiotic resistance development. We investigated how two ciprofloxacin (CIP) impurities, fluoroquinolonic acid (FQA) and ciprofloxacin ethylenediamine analogue (CEA), impact growth and antibiotic resistance in Escherichia coli. Additionally, we investigated how these impurities impact a frequently used API content assay. Both impurities displayed modest antimicrobial activity compared to the CIP API. The effective antimicrobial activity of a medicine containing increased impurity levels may permit bacterial growth and resistance development. Our results also suggest that increasing exposure concentration and duration to CEA and FQA, independent of CIP, can promote antibiotic resistance development. However, at concentrations of 100% and below the MIC of the API, impurities had limited contributions to resistance development compared to the CIP API. From a methodological standpoint, we found that UV spectrophotometry may be inadequate to account for antibiotic impurities or degradation products. This can lead to incorrect estimations of API content and we propose additional multi-wavelength measures when using UV spectrophotometry to help identify impurities or degradation.

Kinetics of generic tacrolimus in heart transplantation: A cautionary note

Tacrolimus is a core component of immunosuppressive regimens. This study compared active pharmaceutical ingredient (API) and dissolution kinetics of branded tacrolimus and formulations from three generic manufacturers (Mylan, Dr. Reddy's, Intas) including samples from patients who suffered acute cardiac allograft rejection. Generic samples showed similar API content compared to branded samples with no major impurities. Capsules that underwent uniformity testing had consistent capsule-to-capsule API. Dissolution testing showed similar profiles between branded tacrolimus and Mylan, but notable differences with Dr. Reddy's and Intas. The approximate maximal inhibitory concentration (IC50) was highest in branded tacrolimus (29 minutes), followed by Mylan (26 minutes), Dr. Reddy's (19 minutes), and Intas (14 minutes) (Student-Newman-Keuls Multiple Comparisons Test; overall ANOVA: p = 0.0199, F = 6.469). This study suggests that the bioavailability of certain generic tacrolimus formulations peak significantly earlier than branded tacrolimus. Further study is needed to determine whether these differences are clinically relevant.

Criticalquality attribute assessment of big brand traditional Chinese medicine: visualization method for quality control of Ginkgo Leaves Tablets based on spatial distribution uniformity

Spatial distribution uniformity is the critical quality attribute(CQA) of Ginkgo Leaves Tablets, a variety of big brand traditional Chinese medicine. The evaluation of the spatial distribution uniformity of active pharmaceutical ingredients(APIs) in Ginkgo Leaves Tablets is important in ensuring their stable and controllable quality. In this study, hyperspectral imaging technology was used to construct the spatial distribution map of API concentration based on three prediction models, further to realize the visualization research on the spatial distribution uniformity of Ginkgo Leaves Tablets. The region of interest(ROI) was selected from each Ginkgo Leaves Tablet, with length and width of 50 pixels, and a total of 2 500 pixels. Each pixel had 288 spectral channels, and the number of content prediction data could reach 1×10~5 for a single sample. The results of the three models showed that the Partial Least Squares(PLS) model had the highest prediction accuracy, with calibration set determination coefficient R_(pre)~2 of 0.987, prediction set determination coefficient R_(pre)~2 of 0.942, root mean square error of calibration(RMSEC) of 0.160%, and root mean square error of prediction(RMSEP) of 0.588%. The classical least-squares(CLS) model had a greater prediction error, with the RMSEP of 0.867%. Multivariate Curve Resolution-Alternating Least Square(MCR-ALS) model showed the worst predictive ability among the three models, and it couldn't realize content prediction. Based on the prediction results of PLS and CLS models, the spatial distribution map of APIs concentration was obtained through three-dimensional data reconstruction. Furthermore, histogram method was used to evaluate the spatial distribution uniformity of API. The data showed that the spatial distribution of APIs in Ginkgo Leaves Tablets was relatively uniform. The study explored the feasibility of visualization of spatial distribution of Ginkgo Leaves Tablets based on three models. The results showed that PLS model had the highest prediction accuracy, and MCR-ALS model had the lowest prediction accuracy. The research results could provide a new strategy for the visualization method of quality control of Ginkgo Leaves Tablets.

The quality assurance of the medicinal composition using the “Antimicrobial activity” indicator

The aim of the work is to determine the spectrum and strenght of antimicrobial activity of the studied compositions, to compare them with the activity of substancesand to select the most optimal concentration for further combination with each other. Topicality. Nowadays, one of the most common skin diseases is acne and demodicosis, the manifestations of which can be mild (comedones in seborrheic areas), more noticeable (papules-pustular rash) and severe (large cyanotic infiltrative elements in the back, prone to abscessing and scarring). The prevalence of acne and demodicosis currently reaches 90%. With these skin pathologies, it is desirable to use safe and effective drugs for external therapy, which provide rapid improvement of the skin (reduction of inflammation without side effects) to obtain a rapid and high-quality therapeutic effect. In the course of our research, we selected 3 active pharmaceutical ingredients (APIs): metronidazole, benzyl benzoate and benzoyl peroxide - according to the purpose of ICD-10 and their effectiveness in these pathologies. Mild medicines have an advantage over dermatological diseases such as acne and demodicosis because the use of soft medicines is local, namely a targeted effect on the microbial microflora. At present for production of soft medicines for local application such substances as macromolecular compounds are widely used, plasticizers, surfactants,etc. When creating a drug composition, a study was conducted aimed at obtaining soft medicines with certain consumer properties, in particular physicochemical (pH, osmotic activity, homogeneity,etc.) , physical and mechanical properties (rheological parameters). Materials for the study – soft medicines based on cetyl alcohol, Emulgade Sucro Plus, Polyvinylpyrrolidone, Carboxymethylcellulose, Tween 80, Triethanolamine, Propylene glycol, vaseline oil, which as (API) contains metronidazole, benzoyl peroxide, benzylbenzene. The specific antimicrobial activity of the samples was tested in accordance with Order № 167 of the Ministry of Health of Ukraine dated 05.04.2007 by the standard macromethod of serial dilutions in liquid nutrient medium and by the method of diffusion into agar. The minimum inhibitory concentration (MIC) of API (substrates) was determined. Results. The studied compositions of soft medicines and substrates revealed to presence of antibacterial (bacteriostatic) action against the test strains of microorganisms. Conclusions. The test of the compositions of soft medicines and the substance revealed the presence of a slight antibacterial (bacteriostatic) effect against the test strains of microorganisms. Key words: antimicrobial activity; active pharmaceutical ingredients (API); excipients; soft dosage form

Substantiation of technology for obtaining capsules of a multi-component drug with neurotropic action

The aim of the work. Theoretical and experimental substantiation of a rational technology for obtaining a preparation in the form of capsules based on uridine-5-monophosphate of disodium salt, cytidine-5-monophosphate of disodium salt, vitamin B6, thioctic acid and magnesium lactate dihydrate, determination of process parameters that can affect critical quality characteristics active pharmaceutical ingredients in the product and establishing acceptance criteria for each critical process parameter to be used in batch production and process control.&#x0D; Materials and methods. Objects of the research: masses for encapsulation, granulates and the finished product - capsules with the conventional name “Neuronucleos”. To obtain capsules, active pharmaceutical ingredients (API) were used: uridine-5-monophosphate disodium salt and cytidine-5-monophosphate disodium salt (Shanghai Oripharm Co. Ltd., China), thioctic acid (Shanghai Modern Pharmaceutical Co., Ltd..”, China), pyridoxine hydrochloride (“DSM Nutritional Products GmbH”, Germany), magnesium lactate (“Moes Cantabra S.L.”, Spain). The quality indicators were studied: description, average mass of content and uniformity of mass, uniformity of dosage units, dissolution, accompanying impurities, quantitative content of API. Methods of liquid chromatography and complexometric titration were used.&#x0D; Results. It has been established that the use of the direct mixing method does not allow obtaining a mass for encapsulation corresponding to the indicator "Bulk density". The use of the wet granulation method in a fluidized bed has been substantiated. It has been shown that it is difficult to perform granulation in a fluidized bed of an API mixture containing thioctic acid. It has been established that it is rational to obtain a mass for encapsulation in two stages: obtaining a granulate from magnesium lactate dihydrate and pyridoxine hydrochloride with a moisturizer solution (sorbitol + uridine-5-monophosphate disodium salt + cytidine-5-monophosphate disodium salt) and then obtaining a mass for encapsulation from granulate, thioctic acid, anhydrous colloidal silicon dioxide and magnesium stearate by the direct mixing method.&#x0D; Conclusions. On the basis of the performed technological research and analysis of the quality of the obtained capsules, a method for obtaining a capsule mass using the method of wet granulation in a fluidized bed was chosen. The granulation mode was substantiated and the optimal parameters for obtaining a high-quality product were selected, the acceptance criteria for each critical parameter of the technological process were established

Real-time release testing of dissolution based on surrogate models developed by machine learning algorithms using NIR spectra, compression force and particle size distribution as input data

In this work spectroscopic measurements, process data and Critical Material Attributes (CMAs) are used to predict the in vitro dissolution profile of sustained-release tablets with three machine learning methods, Artificial Neural Networks (ANN), Support Vector Machines (SVM) and Ensemble of Regression Trees (ERT). Beside the effect of matrix polymer content and compression force, the influence of active pharmaceutical ingredient (API) and matrix polymer particle size distribution (PSD) on the drug release rate of sustained tablets is studied. The matrix polymer PSD was found to be a significant factor, thus this factor was included in the dissolution prediction experiments. In order to evaluate the importance of the inclusion of PSD data, models without PSD data were also prepared and the results were compared. In the developed models, the API and hydroxypropyl-methylcellulose (HPMC) content is predicted from near-infrared (NIR) spectra, the compression force is measured by the tablet press and HPMC particle size is measured off-line. The predictions of ANN, SVM and ERT were compared to the measured dissolution profiles of the validation tablets, ANN yielded the most accurate results. In the presented work, data provided by Process Analytical Technology (PAT) sensors is combined with CMAs for the first time to realize the Real-Time Release Testing (RTRT) of tablet dissolution.

Implementation of the Quality by Design approach for developing the composition and the manufacturing technology of an injectable drug for intra-articular introduction

Aim. To implement the Quality by Design (QbD) approach in order to develop the composition and the manufacturing technology of injectable hyaluronate sodium (HS) in combination with chondroitin sulfate (CS) for intra-articularintroduction. Materials and methods. The composition of the solution for injection was developed using samples of the active pharmaceutical ingredient (API) of HS and CS. The approaches of the ICH international guidelines were used to create the QbD protocol. The quality target product profile (QTPP) was developed based on the literature review, analysis of similar drugs and the previous in-house experimental studies. Determination of critical quality assessment (CQA) product indicators was performed by risk analysis for all quality indicators listed in QTPP. The risk assessment of quality indicators was performed by assessing them according to the Risk Priority Number system (hereinafter – RPN) by a 9-point scale. When studying the composition and the manufacturing technology of the injectable solution the quality risk management (QRM) was developed according to the Ishikawa diagram. Results and discussion. It has been found that the QbD concept is a systematic approach to the drug development. At the first stage QTPP was developed. Based on the QTPP data the CQA indicators were determined, and quality risks were assessed. The critical process parameters (CPP) of the solution for injection based on HS and CS, their control methods, as well as the critical material attributes (CMA) were determined. Based on the data obtained the drug control strategy was proposed taking into account the need to minimize the repetition of control experiments. Using the Isikawa diagram the variability of the material and the process with the environmental factors affecting the qualityof the solution for injection with HS and CS was shown.Conclusions. Using the basic QbD approaches when developing the composition and the manufacturing technology of an injectable drug for intra-articular introduction it has been found that the route of administration, dose, potency, and consumer properties of the product are important aspects of QTPP. It has been proven that the quality indicators, such as transparency, viscosity, sterility and the quantitative content of API are determined as CQA to achieve the objectives defined in QTPP. The study shows that almost all stages of production are critical, therefore, they need to be constantly monitored and checked to obtain a quality product. In further experimental studies to confirm the composition developed and the manufacturing technology according to QRM it is necessary to focus on such indicators as the solution temperature, stabilization time, degassing mode and filtration conditions.

Development and characterization of ibuprofen co-crystals granules prepared via fluidized bed granulation in a one-step process – a design of experiment approach

Objective The focus of this study was to investigate the possibility of producing ibuprofen-nicotinamide (IBU-NIC) and ibuprofen-isonicotinamide (IBU-INA) cocrystal-containing granules, using a one-step fluidized bed dryer granulation manufacturing process, and evaluate their mechanical properties. Significance Pharmaceutical cocrystals represent a suitable strategy to improve properties of active pharmaceutical ingredients (APIs), such as solubility and processability. Ibuprofen (IBU) is a small molecule API which can form cocrystals with different coformers, including NIC and INA. An improvement in mechanical properties for IBU-NIC cocrystals relative to IBU was previously reported but, to date, the formulation of IBU cocrystals in a solid dosage form has not been investigated. Methods In situ cocrystallization and granulation were achieved concurrently by processing in a lab-scale fluidized bed granulator following a design of experiment (DoE) approach using a two-level factorial design with both process and formulation variables. Solid-state, micrometric, dissolution, and mechanical (tabletability) characteristics of granules were assessed post-processing. Results Granules containing cocrystals were successfully prepared for 11 of 16 DoE runs. Parameters with a significant effect on granule drug loading, flow function, porosity, and size could be identified from the DoE model. Process yield was increased by using a high inlet temperature at high solution feed rate. To avoid the formation of sticky particles, caking and over-wetting of the powder during the process, the utilization of high inlet temperature, low API + coformer:filler ratio, low API concentration in solution and low solution feed rate were suggested by the model. Conclusion The multivariable model developed enables accurate optimization of the granulation process for IBU cocrystals.

Comparative Antibacterial Activity of Five Brands of Ciprofloxacin Injectables in Nigeria

Background: Ciprofloxacin, a widely used antimicrobial agent, is available in Nigeria in various tablet and injectable dosage forms. In this era of fake and substandard drugs, it is important to be sure of the quality and antimicrobial potency of ciprofloxacin injectables imported and sold in Nigeria.Objectives: This study is aimed at evaluating and comparing the antibacterial efficacy of five different brands of ciprofloxacin infusion available in Nigeria against clinical bacterial isolates.Method: Ultraviolet-visible (UV-VIS) spectroscopy was used to determine the percentage content of active pharmaceutical ingredient in each brand, while antibacterial activities were compared against five bacterial strains including: Escherichia coli (E), Klebsiella pneumoniae (K), Pseudomonas aeruginosa (Ps), Proteus mirabilis (Pr), Staphylococcus aureus (St) and Salmonella typhi (Sa). Minimum inhibitory concentrations (MICs) and the minimum bactericidal concentration (MBCs) were determined by broth dilution method. Statistical analysis of the results obtained was done by ANOVA.Result: The percentage content of all the five brands of ciprofloxacin injection was not less than the specification (95-105%) of the British Pharmacopoeia, BP (2009). The susceptibility test showed that 16 out of 30 (53.3%) isolates were multidrug resistant. Ciprofloxacin was active on most of the clinical isolates which justify its wide use in treating infections in Nigeria; however, resistance to ciprofloxacin is increasing.Conclusion: Comparing the different brands, there was slight variation but no significant difference (p&gt; 0.05) in their antibacterial activity (p= 0.96, 0.999 for sensitivity at 10μg/ml and MIC respectively).&#x0D; Keywords: Ciprofloxacin brands, Fake drugs, Physicochemical analysis, Antibacterial, Antimicrobial resistance

Continuous blending monitored and feedback controlled by machine vision-based PAT tool

In a continuous powder blending process machine vision is utilized as a Process Analytical Technology (PAT) tool. While near-infrared (NIR) and Raman spectroscopy are reliable methods in this field, measurements become challenging when concentrations below 2 w/w% are quantified. However, an active pharmaceutical ingredient (API) with an intense color might be quantified in even lower quantities by images recorded with a digital camera. Riboflavin (RI) was used as a model API with orange color, its Limit of Detection was found to be 0.015 w/w% and the Limit of Quantification was 0.046 w/w% using a calibration based on the pixel value of images. A calibration for in-line measurement of RI concentration was prepared in the range of 0.2−0.45 w/w%, validation with UV/VIS spectrometry showed great accuracy with a relative error of 2.53 %. The developed method was then utilized for a residence time distribution (RTD) measurement in order to characterize the dynamics of the blending process. Lastly, the technique was applied in real-time feedback control of a continuous powder blending process. Machine vision based direct or indirect API concentration determination is a promising and fast method with a great potential for monitoring and control of continuous pharmaceutical processes.

A QbD and Green Analytical Chromatography Technique for the Determination of Active Pharmaceutical Ingredient, Preservative and Antioxidant Contents in Lincosamide Antibiotic Injectable Formulation

A QbD and Green Analytical Chromatography Technique for the Determination of Active Pharmaceutical Ingredient, Preservative and Antioxidant Contents in Lincosamide Antibiotic Injectable Formulation