Final Dosage Form Research Articles

Leveraging solid solubility and miscibility of etoricoxib in Soluplus® towards manufacturing of 3D printed etoricoxib tablets by additive manufacturing

This research focuses on exploring the solid solubility and miscibility of Etoricoxib, a poorly water-soluble anti-inflammatory drug, within Soluplus®, a polymer used as a matrix for 3D-printed tablets. By utilizing hot-melt extrusion (HME), the drug was dispersed within Soluplus® to enhance its solubility. The extrudates were then employed in 3D printing to create customized solid oral dosage form. This study’s novelty lies in combining HME and 3D printing, aiming to improve drug incorporation, stability, and effectiveness in the final formulation. Comprehensive characterization techniques, including hot stage microscopy (HSM), scanning electron microscopy (SEM), micro-computed tomography (Micro-CT), florescence microscopy, optical microscopy, X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), solubility studies, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and aqueous solubility study were utilized to elucidate the physicochemical properties, thermal stability, and structural integrity for the extruded filaments (the printing ink), and 3D printed tablets made thereof. Furthermore, the in vitro drug release profile of the 3D printed tablet was systematically evaluated, revealing a controlled drug release pattern from the finished dosage form. The systematic investigation reported herein, starting from theoretical miscibility to the printing ink development through HME, detailed characterization of the extruded filaments, and further solid oral formulation development by additive manufacturing can be utilized as a platform technology or a pathway for the development of personalized medicine with drugs having similar physicochemical properties.

Pre-formulation Characteristics of Ticagrelor: A Comprehensive Exploration

Ticagrelor is a potent antiplatelet agent that plays a crucial role in preventing cardiovascular events. Preformulation studies are essential in the drug development process to assess the physicochemical properties of the active pharmaceutical ingredient (API) and its suitability for formulation into a final dosage form. This abstract provides an overview of the preformulation studies conducted on Ticagrelor. The preformulation studies encompassed an extensive analysis of Ticagrelor's physical properties, including solubility, melting point, and crystal structure. Additionally, the drug's stability under various environmental conditions, such as temperature and humidity, was evaluated. Spectroscopic techniques, such as UV-Vis and FTIR, were used to characterize the chemical structure of the compound. The results of these preformulation studies provide valuable insights into the potential challenges and opportunities in formulating Ticagrelor into stable and bioavailable dosage forms. These findings will guide further formulation development and optimization, ensuring the delivery of an efficacious and safe drug product to patients.

Study of integration processes in the pharmaceutical market in the context of the development of territorial pharmaceutical ecosystems

Introduction. The ecosystem approach to the organization of business processes in the pharmaceutical market meets the prevailing trends, so the growth index of e-commerce in the retail sector of medicines for 5 years amounted to 1.87. The market distribution sector of medicines in the Russian Federation is characterized by a shift in corporate governance towards marketing cooperation based on aggregation electronic trading platforms (AETPS). Development of territorial pharmaceutical ecosystems (TFE) As a new integrative tool for managing the pharmaceutical development – production – distribution cycle, in order to achieve the target model of PHARMA 2030 at the territorial level, it requires the development of regulatory mechanisms for managing the supply of medicines. Objective: characteristics of integration processes in the industrial, wholesale and retail sectors of the pharmaceutical market to assess the potential competitiveness of territorial pharmaceutical ecosystems. Material and methods. The primary data for the analysis were: volumes of wholesale commodity residues of medicines produced in the Ural Federal District (461 registration certificates; proprietary Price and Distribution Test data for 230 trade names of LP EMIS data 2021–2022; Alpharm data 2021–2022; Datainsight 2022. In the course of the study, a structural analysis of the pharmaceutical market, a functional analysis of participants in the pharmaceutical product chain, and a marketing analysis were carried out. Results. It was found that the dynamics of the AETP segment development corresponds to the outstripping growth of highly integrated platforms: the short-term growth index of 5-pl AETP (Uteca) is 164%, 4-pl (Eapteca) is 55%, 3pl-AETP (averaged) is 36.5%. The absence of formal mechanisms of regional protectionism for the sale of finished dosage forms of local manufacturers in the Ural Federal District has been revealed. We have obtained the results of evaluating the effect of ecosystem integration of certain types of pharmaceutical market participants. For manufacturers of medicinal products, it was determined that the median coefficient of penetration of the local assortment of medicinal products into the pharmaceutical market in the context of ATX groups of level 2 is 0.67, which indicates a significant diversification of the assortment portfolio and the possibility of its aggregation without a barrier of internal competition. In the wholesale drugs sector, the potential for saving margins on medicines has been identified when implementing the scenario of localization of supplies in production regions in low and medium-low price ranges (30 – 550 rubles/unit), varying between 53–67%. It was found that the median share of regional distribution in the Ural Federal District (in packages) is 20.72%. It has been established that the Ural Federal District is one of the leaders in terms of the share of omnichannel consumers in the pharmaceutical market (63%), which is a significant incentive for the integration of organizations in the retail sector of the pharmaceutical market into the ecosystem 5pl platform. Conclusion. Situational analysis of the morphology of cooperative interactions in the pharmaceutical market allowed us to identify the prerequisites for the formation of ecosystem-organized management structures in the pharmaceutical market system – territorial pharmaceutical ecosystems. We have systematized incentives for ecosystem determination of medicines supplies, and found that: an additional channel for the market distribution of the industrial range of medicicnes in the Urals is not associated with a barrier to internal competition of pharmaceutical plants; the inclusion of regional suppliers in TFE will allow to form additional competitiveness in the “buyer's market” in conditions of market dominance of federal suppliers; the omnichannel approach to the distribution of the retail range of TFE in pharmacy organizations has a high projected conversion rate. A detailed assessment of integration processes in certain sectors of the pharmaceutical market did not reveal critical barriers to the introduction of TFE.

Development and validation of UV-spectrophotometry method for quantitative determination of amorphous darunavir

Introduction. Darunavir as an effective antiretroviral drug is widely used in clinical practice, including for the treatment of pediatric patients, as well as pregnant women, and for personalized therapy. Currently darunavir is used in the production of finished dosage forms, both in the form of crystalline ethanolate and in the form of an amorphous substance. In this regard, there is a need to develop and improve methods for the quantitative determination of darunavir. As an inexpensive and effective alternative to common chromatographic and titrimetric methods, spectrophotometric determination of darunavir in the ultraviolet region of the spectrum (UV spectrophotometry) may be used.Aim. To develop and validate a method for the quantitative determination of amorphous darunavir in the substance by UV spectrophotometry.Materials and methods. The following substances and consumables were used for the research: powdered amorphous darunavir substance (USP); darunavir reference standard (MSN Pharmachem Pvt. Ltd., India); methanol for HPLC Gradient Grade 99.9 % (High purity); acetonitrile for HPLC Gradient Grade 99.9 %; glacial acetic acid for HPLC; 0.1 M perchloric acid solution (in anhydrous acetic acid) for titration in non-aqueous media; nylon syringe filters with a pore diameter of 0.22 microns. Spectrophotometric determination of darunavir was carried out using an Cary 60 spectrophotometer (Agilent Technologies, USA) and a UNICO 2800 spectrophotometer (United Products & Instruments, Inc., USA). To prepare standard solutions, we used analytical balance Analytical Balance MS105/A (METTLER TOLEDO, Switzerland), analytical balance GH-120 (AND, Japan) class A measuring glassware, graduated pipettes ISOLAB.Results and discussion. The method was developed and validated for the following characteristics: specificity, linearity, accuracy, precision, analytical range. According to the study results, the main validation characteristics of the method meet the acceptance criteria.Conclusion. A new method for the quantitative determination of amorphous darunavir by UV spectrophotometry was successfully developed and validated. The method may be used to control the quality of substances of amorphous darunavir, including the intrapharmaceutical control.

Separation and Validation of Comprehensive Impurities in Erythromycin Tablets by using Rp-HPLC method

In this study a simple, rapid, accurate and precise gradientRP-HPLC method has been developed and validated for the separation of impurities (IMP) in Erythromycin (ERT-A) tablets pharmaceutical dosage form. The chromatographic separation was carried out on WatersX-Terra RP 18 (250 mm x 4.6 mm I.D., 3.5 µm particle size) at 65°C was used for this separation. Mobile Phase-A consists of Buffersolution (35 g of di-potassium hydrogen phosphate in 1000mL of water, adjust the pH7.0with dilute o-phosphoric acid, filtered through 0.45 µm membrane filter) acetonitrile and water in ratio of 5:35:60 v/v/v respectively. Mobile Phase-B consists of a mixture of phosphate buffer pH 7.0, water and acetonitrile in ratio of 5:45:50 v/v/v respectively .The flow rate and injection volume was 1.0 mL/min and 100 μL respectively. The analysis was carried out under the gradient conditions as time (min)/A (v/v): B(v/v); T0/100:00, T45/100:00, T47/0:100, T63/0:100, T65/100:00, and T70/100:00. The wavelength was identified at 215 nm. The ERT-Adegrades under various circumstances. The degradation products were well resolved from the ERT peaks. This method was found to be linear. The cumulative %RSD values are ;identified and found that they are within the range. From the study concluded that the method is accurate, specific, selective, precise, robust, and useful during the process development and quality check in finished dosage form manufacturing.

Analysis of the accumulation of β-emitting radionuclides in the production of radiopharmaceuticals based on <sup>18</sup>F using the IBA CYCLONE 18/9 HC cyclotron

In order to clarify the scheme of radioactive waste management, the accumulation of undesirable beta-emitting radionuclides (PH) in the production of radiopharmaceuticals based on 18F using the IBA CYCLONE 18/9 HC cyclotron was investigated. It is shown that the dominant impurity PH is tritium, which is formed by the reaction of 18O(p, t) 16O when water is irradiated with [18O]H2O protons. The main proportion of 3H (about 95%) remains in the regenerated water. 1.6 % of the accumulated tritium activity is carried away from the synthesis zone with gases and water vapor. Tritium-containing waste (regenerated water in vials) can be considered as waste of a very low level of activity during disposal. With an increase in the operating time of the target over 2500 µA · h, the processes of corrosion /erosion of target materials increase, which leads to a sharp increase in the concentration of undesirable radionuclides in regenerated water, sorption purification cartridges and the finished dosage form. The concentration of tritium does not increase significantly. In the β-spectra of regenerated water [18O]H2O and the finished radiopharmaceutical [18F]NaF, in addition to the maximum due to tritium, a number of maxima appear in both the low- and high-energy parts of the spectrum. Other undesirable β-emitters accumulate in water as a result of leaching of the activated target wall. The possibility of using measurements of tritium activity in water [18O]H2O as an indicator of its re-enrichment has been demonstrated. The necessity of controlling the content of impurity beta-emitting PH in intermediate products, production waste and final radiopharmaceutical is shown.

Technology criteria for the manufacturing of Rebamipide film-coated tablets

Introduction. In the modern world, there are many pharmaceutical substances that have various structure. During the development of finished dosage forms (FDPs) it is necessary to take into account many factors, such as physicochemical and technological properties of substances and excipients, manufacturing technology and others. This work is focused on the application of these approaches in practice in relation to a substance with anisodiametric crystal shape. Rebamipide was chosen as an example of such substance with poor technological characteristics for investigation and manufacturing technology selection.Aim. Research of approaches to examine a substance with anisodiametric crystal shape (Rebamipide in this case) to determine its physicochemical and technological properties in purpose of theoretical substantiation of the best method of manufacturing mass for tabletting.Materials and methods. In this study were used such materials as Rebamipide substance (α-[(4-chlorobenzoyl)amino]-1,2-dihydro-2-oxo-4-quinolinepropanoic acid) (experimental sample). Also were used such equipment as flowability tester ERWEKA GT (Erweka GmbH, Germany), powder density tester ERWEKA SVM 122 (ERWEKA GmbH, Germany), vibrating sieve CISA RP 200N (CISA Cedaceria Industrial S.L., Spain), powder diffractometer D8 ADVANCE (Bruker Corporation, USA), calorimeter DSC 204 F1 (NETZSCH, Germany), Hitachi TM-100 electron microscope (Hitachi, Japan).Results and discussion. The properties of Rebamipide substance were evaluated, such as polymorphism, melting point, microscopy and evaluation of technological characteristics. Application of the SeDeM method allowed to determine the critical parameters of the substance that need to be corrected.Conclusion. It was found out experimentally that Rebamipide substance has polymorphism, high melting point, needle-shaped crystals, poor bulkiness and compactability, which was confirmed by the use of SeDeM method.

Development of dexibuprofen loaded nano transfersomal gel with enhanced biopharmaceutical performance in complete Freund's adjuvant induced arthritis model

The purpose of this study was to enhance the biopharmaceutical performance of Dexibuprofen (DXI) using transfersomal gel (DXI-TG) as drug delivery system. DXI loaded transfersomes (DXI-T) were prepared via thin film technique, characterized for particle size, polydispersity index, zeta potential, particle morphology and entrapment efficiency. The DXI-T was further incorporated into 2 % (w/v) chitosan gel to get the final dosage form DXI-TG, which was characterized for homogeneity, pH, spread-ability and rheological properties. In vitro release, ex vivo permeation and in vivo studies were also conducted along with stability study of the optimized formulation. DXI-T showed excellent vesicle properties including, size distribution (235.1 ± 4.66 nm), poly dispersity index (0.184 ± 0.001), zeta potential (−10.5 ± 0.23 mV) and entrapment efficiency (82.9 ± 1.07 %). TEM analysis exhibited spherical morphology and uniformly distributed nanoparticles, whereas FTIR showed no bond anomalies. DXI-TG showed suitable gel properties with a viscosity of 11310 ± 20 cP, pH 5.2 ± 0.3, good homogeneity, non-Newtonian flow behavior, good spread-ability (298 ± 7.63 %) and high drug content (97.01 ± 3.1 %). in vitro release studies demonstrated that DXI-TG has significantly controlled the release of DXI when compared with DXI-T, DXI-G and DXI-Suspension at pH 5.5 and 7.4. Similarly, ex vivo permeation analysis showed meaningfully increased permeation of DXI-T followed by DXI-TG when compared with test formulations. Like normal control group, skin irritation studies showed no erythema and edema in DXI-TG treated group. Additionally, DXI-TG demonstrated a significantly enhanced bioavailability (5-fold) when compared with DXI-Suspension and DXI-G. Furthermore, DXI-TG showed significantly enhanced therapeutic effect against acute arthritis model when compared with DXI-Suspension and DXI-G. Besides, no signs of evident toxicity on major body organs was observed in DXI-TG treated animal group. Also, the DXI-TG was found stable for a period of 6 months. It can be concluded that transfersomal gel may be a suitable carrier for DXI with enhanced bioavailability, improved therapeutic efficacy and no evident toxicity as exhibited in this study.

Microfluidics-on-a-chip for designing celecoxib-based amorphous solid dispersions: when the process shapes the product

AbstractThe fundamental idea underlying the use of amorphous solid dispersions (ASDs) is to make the most of the solubility advantage of the amorphous form of a drug. However, the drug stability becomes compromised due to the higher free energy and disorder of molecular packing in the amorphous phase, leading to crystallization. Polymers are used as a matrix to form a stable homogeneous amorphous system to overcome the stability concern. The present work aims to design ASD-based formulations under the umbrella of quality by design principles for improving oral drug bioavailability, using celecoxib (CXB) as a model drug. ASDs were prepared from selected polymers and tested both individually and in combinations, using various manufacturing techniques: high-shear homogenization, high-pressure homogenization, microfluidics-on-a-chip, and spray drying. The resulting dispersions were further optimized, resorting to a 32 full-factorial design, considering the drug:polymers ratio and the total solid content as variables. The formulated products were evaluated regarding analytical centrifugation and the influence of the different polymers on the intrinsic dissolution rate of the CXB-ASDs. Microfluidics-on-a-chip led to the amorphous status of the formulation. The in vitro evaluation demonstrated a remarkable 26-fold enhancement in the intrinsic dissolution rate, and the translation of this formulation into tablets as the final dosage form is consistent with the observed performance enhancement. These findings are supported by ex vivo assays, which exhibited a two-fold increase in permeability compared to pure CXB. This study tackles the bioavailability hurdles encountered with diverse active compounds, offering insights into the development of more effective drug delivery platforms. Graphical Abstract

A multi-analyte assay of opioids in API and drug products using HPLC and HRMS

Surveillance testing is an essential component to ensuring safe, effective, and high-quality drug products are available in the commercially marketed US supply chain. Surveillance allows the agency to assess product quality and monitor for potential adulteration of drug products being used by consumers. Opioid drug products can be adulterated to enhance the effect of the intended active ingredient. Numerous accounts have been reported where fentanyl has been used as an adulterant in illicit street drugs such as heroin, cocaine, or methamphetamine. To efficiently surveil the legitimate opioid supply chain, an analytical method with the ability to simultaneously detect, identify and quantify opioid molecules is desired. In this study, a multi-opioid protocol (MOP) using liquid chromatography-high resolution mass spectrometry (HPLC-HRMS) technology was developed and validated for the detection and quantification of 27 opioid drugs.The MOP analytical procedure was applied to the analysis of drug substance and finished dosage forms. MOP was used to identify and quantify active pharmaceutical ingredients (API) listed on the label claim, and in the case of suspected economically motivated adulteration could identify and quantify undeclared opioid APIs. The analytical method analysis time was 16 minutes and the LOD and LOQ in full MS mode were (average) 0.3 and 0.8 ng/mL, respectively. The validation criteria parameters were satisfactory based on international guidelines (ICH).The MOP was successfully applied to the analysis of over 160 drug substances and finished products. For all samples tested in the study, their identities were confirmed, and assays met specifications. Overall, there was no evidence of illegal substitution or adulteration in any of the ingredients and products tested from the legitimate commercial marketed US supply chain.

Development and validation of stability indicating ultra‐high‐performance liquid chromatographic method for assay and impurities of mexiletine hydrochloride and mexiletine hydrochloride capsules

AbstractMexiletine (MEX) is an antiarrhythmic drug used to treat acute and chronic ventricular arrhythmias. A simple isocratic, rapid, specific, stability‐indicating, and sensitive reverse‐phase ultra‐high‐performance liquid chromatography (UHPLC) method was developed and successfully validated to quantify the assay and impurities of MEX hydrochloride. The new UHPLC method showed the optimum separation of MEX and its seven impurities in 20 min by using sodium acetate buffer (0.14 mM) with 0.3% of glacial acetic acid (pH 4.8) and methanol in the ratio of 40:60 (v/v) as mobile phase. The method used an Acquity HSS T3 (100 × 3.0 mm, 1.8 µm) chromatographic column at a 0.2 mL/min flow rate. The injection volume is 2 µL, and 254 nm is the detection wavelength. Note that, 25°C is the column oven temperature. The method is linear over the concentration range of the quantification limit (0.03%) to 150% (0.3%) of the specification level (0.2%) for the impurities and 50%–150% for the assay method. The quality control lab of bulk drugs and finished dosage form successfully applied the new UHPLC method for quantification of assay and impurities of MEX hydrochloride.

Accelerative Solid-State Oxidation Behaviour of Amorphous and Partially Crystalline Venetoclax.

There is a growing focus on solid-state degradation, especially for its relevance in understanding interactions with excipients. Performing a solid-state degradation of Venetoclax (VEN), we delve into VEN's stability in different solid-state oxidative stress conditions, utilizing Peroxydone™ complex and urea peroxide (UHP). The investigation extends beyond traditional forced degradation scenarios, providing insights into VEN's behavior over 32h, considering temperature and crystallinity conditions. Distinct behaviors emerge in the cases of Peroxydone™ complex and UHP. The partially crystalline (PC-VEN) form proves more stable with Peroxydone™, while the amorphous form (A-VEN) shows enhanced stability with UHP. N-oxide VEN, a significant degradation product, varies between these cases, reflecting the impact of different oxidative stress conditions. Peroxydone™ complex demonstrates higher reproducibility and stability, making it a promising option for screening impurities in solid-state oxidative stress scenarios. This research not only contributes to the understanding of VEN's stability in solid-state but also aids formulators in anticipating excipient incompatibilities owing to presence of reactive impurities (peroxides) and oxidation in the final dosage form.

IN VITRO PERMEABILITY STUDY OF NASAL MEDICINAL PRODUCT FOR SYSTEMIC ACTION

For systemic medicinal products bioavailability is a fundamental characteristic that determines their efficacy and onset of action. Biopharmaceutical parameters of nasal preparations (physicochemical properties of the active substance such as membrane permeability, solubility, lipophilicity, pKa, polymorphic state, type of finished dosage form, pH, osmolarity, composition and characteristics of excipients), affecting bioavailability, are variable and controllable within pharmaceutical development. Besides the use of components that affect enzymatic activity, mucoadhesion and effective con-tact time, mucociliary clearance and viscosity of mucous secretion, changing the rate and degree of absorption of the active substance is possible by modulation of tight junctions and paracellular transport. These processes can be particularly determined by the osmolarity of the dosage form and the use of permeation enhancers. Taking into account the portfolio of excipients available to scientists used in a wide range of concentrations, and, in addi-tion, the requirements of the target product profile in terms of safety and pharmacokinetic parameters, as well as regulatory recommendations for jus-tification of the composition within pharmaceutical development, with particular emphasis on the selection of functional components and the concen-trations used, it is important to have relevant and reliable screening tools when formulating a drug product. Due to the absence of standard bioavailabil-ity assessment methods for nasal preparations, literature review was conducted and methodology of in vitro permeability study for of nasal medicinal products for systemic action with the use of artificial membranes as well as cell line RPMI 2650 of human nasal epithelium is developed. The use of such sufficiently homogeneous barrier films allows to minimize the variability of test conditions. Permeation study of developed compositions of an-timigraine medicinal product is conducted. The results obtained provide evidence of their qualitative compliance and allow to recommend laboratory permeability study on cellulose membranes for the selection and justification of the composition of pharmaceutical compositions. Bioavailability is a fundamental characteristic of pharmaceutical products for systemic action, which defines efficacy and speed of action. Permeability through biological membranes is defined not only by the properties of active component but also by the particulars of formulation. Due to the absence of standard bioavailability assessment methods for nasal preparations, literature review was conducted and methodology of in vitro permeability study for of nasal medicinal products for systemic action with the use of artificial membranes as well as cell line RPMI 2650 is developed. Permeation study of developed compositions of antimigraine medicinal product is conducted. The results obtained provide evidence of their qualitative compliance and allow to recommend laboratory permeability study on cellulose membranes as a screening tool in pharmaceutical development.

Development and characterization of plant derived wastes Nano-formulation loaded in thermo-reversible gel for burn healing: An effort towards Sustainable Development

The duty of research is to suggest solutions to ailments affecting humans. Recently, there has been a demand that these solutions should be environmentally responsible, eco-friendly and coincide with sustainable development goals. From this perspective, the objective of this study was to develop thermo-reversible and healing promoting gel formulations. The gel base incorporated Natural Plant derived Wastes’ ethanolic extracts of either Kiwi peels (KE) or Yucca seeds (YE) (antioxidant, vitamins and anti-inflammatory natural agent) loaded chitosan nanoparticles for enhancement of burn healing performance. Comparative evaluation was done to all formulations to find the best competitor to conventional marketed drug formulations. Both extracts were standardized using HPLC. The lipoid content of YE was investigated using GC-MS, showing a content of 32.78 and 15.7 %of linoleic and pamiticmethyl esters, respectively. The nanoparticles characterization and the in-vitro physicochemical characteristics of the final dosage form formulations were assessed, revealing86.65 and 76.6 % entrapment efficiency, 311.4 and 198.1 nm particle size for KE and YE nanoformulations, respectively. The efficacy of the formulations was investigated in vivo against the commercial burn healing drug Mebo®, biochemical parameters and histopathology were statistically investigated. Reduction in wound area reached 69.12 and 72.01 % on day 12 for KE and YE nanoformulations, respectively. The YE encapsulated within chitosan nanoparticles loaded gel showed a promising and a significant healing effect comparable to the most commonly used marketed drug product (Mebo®) and possible mechanisms involved in the phases of healing were illustrated. Eco-friendly waste herbal extracts-loaded chitosan nanoparticles in thermo-reversible gel have been successfully developed from the two extracts: Kiwi peels and yucca seeds for burn and wound healing. This confirms the possible use of traditional medicines in advanced formulations to satisfy the future market of pharmaceuticals.

Analysis of Biopharmaceutical Manufacturing Localisation in Russia Considering the Country of Origin of Active Pharmaceutical Ingredients

SCIENTIFIC RELEVANCE. Russia is pursuing a consistent government policy of import substitution and increasing the localisation of pharmaceutical manufacturing. The Strategy for the Development of the Pharmaceutical Industry until 2030 (Pharma-2030) includes the target share of medicinal products from the List of Strategic Medicines that should be fully localised. Since biotechnological medicinal products have high consumption growth rates and are listed as strategic medicines, it is a priority to study their production localisation process.AIM. This study aimed to analyse the degree of biopharmaceutical manufacturing localisation in Russia, considering the country of origin of active pharmaceutical ingredients (APIs).MATERIALS AND METHODS. The study used the State Register of Medicines and sales data of the DSM Group marketing agency. The authors used custom software for the Node.js® platform to determine the degree of production localisation.RESULTS. The analysis showed that the production process was fully localised for 25.6% (in packages) and 26.6% (in roubles) of all biotechnological medicinal products consumed in Russia in 2022. Imported medicinal products dominated the consumption structure, with a share of 33.9% in packages and 31.3% in roubles. Medicinal products with localised secondary packaging accounted for 5.8% in packages and 25.9% in roubles. Finished dosage forms produced using imported APIs had a significant share of 23.7% in packages and 6.2% in roubles. Russian APIs were used to produce 79% of the biotechnological medicinal products listed as strategic medicines, which corresponded to the full localisation of a share of the consumption structure of 10.8% in packages and 32.3% in roubles.CONCLUSIONS. The Russian biotechnological market remains heavily dependent on imported finished medicinal products and APIs. Although the Pharma-2030 target for the production of strategic biotechnological products has been achieved, the quantitative indicators show the necessity to increase output and localisation.

Development of Ternary Amorphous Solid Dispersions Manufactured by Hot-Melt Extrusion and Spray-Drying─Comparison of In Vitro and In Vivo Performance.

Producing amorphous solid dispersions (ASDs) by hot-melt extrusion (HME) is favorable from an economic and ecological perspective but also limited to thermostable active pharmaceutical ingredients (APIs). A potential technology shift from spray-drying to hot-melt extrusion at later stages of drug product development is a desirable goal, however bearing the risk of insufficient comparability of the in vitro and in vivo performance of the final dosage form. Hot-melt extrusion was performed using API/polymer/surfactant mixtures with hydroxypropyl methylcellulose acetate succinate (HPMCAS) as the polymer and evaluated regarding the extrudability of binary and ternary amorphous solid dispersions (ASDs). Additionally, spray-dried ASDs were produced, and solid-state properties were compared to the melt-extruded ASDs. Tablets were manufactured of a ternary ASD lead candidate comparing their in vitro dissolution and in vivo performance. The extrudability of HPMCAS was improved by adding a surfactant as plasticizer, thereby lowering the high melt-viscosity. d-α-Tocopheryl polyethylene glycol succinate (TPGS) as surfactant showed the most similar solid-state properties between spray-dried and extruded ASDs compared to those of poloxamer 188 and sodium dodecyl sulfate. The addition of TPGS, however, barely affected API/polymer interactions. The in vitro dissolution experiment and in vivo dog study revealed a higher drug release of tablets manufactured from the spray-dried ASD compared to the melt-extruded ASD; this was attributed to the different particle size. We could further demonstrate that the drug release can be controlled by adjusting the particle size of melt-extruded ASDs leading to a similar release profile compared to tablets containing the spray-dried dispersion, which confirmed the feasibility of a technology shift from spray-drying to HME upon drug product development.

VALIDATION EVALUATION OF THE METHOD OF QUANTITATIVE DETERMINATION OF α(1,2)-L-RHAMNO-α(1,4)-D-GALACTOPYRANOSYLURONANE ACORUS CALAMUS L. IN DOSAGE FORM

Introduction. The object of increased attention of researchers is calamus (Acorus calamus L.), for the components of which a wide range of pharma-cological activities have been identified – immunomodulatory, anti-inflammatory, analgesic, antioxidant, neuroprotective, hypolipidemic, antitumor. Ac-cording to previous studies, it was found that α(1,2)-L-rhamno-α(1,4)-D-galactopyranosyluronan, isolated from the rhizomes of Acorus calamus L., has antimetastatic, antiblastoma, and immunomodulatory properties. The substance can also reduce the toxic effect on the hematopoietic system and in-crease the effectiveness of chemotherapy. Based on it, a finished dosage form was obtained - a solution for intravenous administration of 10 mg/ml, which requires the development of valid quality control methods for inclusion in the draft regulatory document on the quality and registration of a new drug. The aim of the study was to determine the metrological characteristics of the chromatographic technique for the quantitative determination of α(1,2)-L-rhamno-α(1,4)-D-galactopyranosyluronan in the finished dosage form. Material and methods. The object of the study was the finished dosage form - a solution for intravenous administration of α(1,2)-L-rhamno-α(1,4)-D-galactopyranosyluronan Acorus calamus L. 10 mg/ml, produced on the basis of the educational establishment of the Technology Implementation Cen-ter of the Federal State Budgetary Educational Institution of Higher Education of the Siberian State Medical University of the Ministry of Health Russia. Quantitative determination was carried out using a Dionex Ultimate 3000 liquid chromatograph (Thermo, Germany) with a refractometric detector RI-101. Validation assessment was carried out according to the following indicators: linearity, accuracy, precision under repeatability conditions. Results. Linear regression analysis of the obtained results using the least squares method showed that the technique is linear in the concentration range of 80–120%. When determining the accuracy, the openability for concentrations of 80, 100 and 120% varied in the range of 99.68–101.96%. The values of the relative standard deviation did not exceed the permissible values when assessing precision 0.82–4.51%. Conclusions. The methodology is valid for the studied indicators and can be recommended for inclusion in the draft regulatory document on quality. The work was carried out within the framework of applied scientific research 720000F.99.1.BN62AB30000 within the framework of state assignment No. 056-00116-23-01.

Good manufacturing practice in low‐ and middle‐income countries: Challenges and solutions for compliance

AbstractApproximately 2 billion people globally have limited access to essential medicines, particularly those living in low‐ and middle‐income countries (LMICs). In addition, there is a higher prevalence of substandard and counterfeit medicines in LMICs, which may cause antimicrobial resistance and therapeutic failure. Good manufacturing practice (GMP) is key to ensuring access to high‐quality, safe and effective medicines, including active pharmaceutical ingredients and excipients used for manufacturing finished dosage forms. Compliance with GMP standards saves resources for both manufacturers (e.g. avoiding expensive product recalls) and governments (e.g. minimising compliance inspections). Concerted collaborations among different countries to harmonise GMP standards and procedures have occurred, and the World Health Organisation (WHO) GMP is commonly used in LMICs. However, barriers to GMP compliance remain apparent, particularly in LMICs. Pharmaceutical manufacturers in LMICs face several barriers such as inadequate resources and infrastructure, inefficient or weak regulation, a shortage of skilled people and limited training opportunities for manufacturing personnel. Although national regulatory authorities (NRAs) have been established in LMICs, most NRAs are not fully independent and are placed within the health department. NRAs in LMICs are not able to fully utilise international and regional reliance mechanisms and collaborations. Therefore, both NRAs and pharmaceutical manufacturers must be adequately supported through resources, infrastructure and capacity‐building opportunities. NRAs must be suitably empowered with assured functional independence. A comprehensive guideline for managing conflicts of interest among pharmaceutical manufacturers, procurement agencies and NRAs is needed. NRAs must liaise with other NRAs, participate in joint GMP inspections and leverage the expertise of regional or international collaborations. Pharmaceutical manufacturers in LMICs can leverage WHO GMP standards to improve GMP compliance and expand their market. However, as these solutions may have cost implications, prioritising key gaps for GMP compliance and optimisation of available resources are essential.

Selection of excipients for the formulation of varenicline tablet cores

The active pharmaceutical ingredient (APS) of varenicline is a tartrate with the chemical name 7,8,9,10‑Tetrahydro-6,10‑Methano-6H-pyrazino(2,3‑h) (3)benzazepine (as tartrate). Varenicline free base is an achiral molecule, however varenicline tartrate, which is formed by the reaction of varenicline free base and L-tartaric acid, is optically active and has an absolute counterion configuration of 2R, 3R. At the moment, only the drug Champix, produced by the pharmaceutical company Pfizer, is represented among direct analogues, so the development of a domestic analogue is an urgent topic of research. The purpose is to develop the optimal composition of varenicline tablet cores to create a finished dosage form.

Formulation and Evaluation of Nanosponge-based Drug Delivery System of Aceclofenac for Topical application

A transdermal drug delivery system using nanosponge and BCS class II drug, Aceclofenac (ACE) was achieved using xerogel as a final dosage form. Blank Beta Cyclodextrin based nanosponge (CDNS) were loaded with aceclofenac to formulate ACE loaded CDNS not only can be effectively treated for osteoarthritis but also successfully evaluated using ex vivo skin permeation studies. Methods used for formulation of ACE loaded CDNS were found out to be effective and accomplished 89.29±2.59% drug entrapment. The optimized formulation had % drug loading of 72.16±3.13%. The zeta potential of the ACE-loaded CDNS was found to be -27.3±1.1mV. A zeta potential value close to ±30mV indicates good physical stability of the micro particles on account of electrostatic repulsion. ACE-loaded CDNS released more than 90% drug in just 150mins (2.5hrs) whereas the marked formulation and ACE drug released more than 90% drug in 240mins (4hrs) and 330mins (5.5hrs) respectively. The conclusion of the current work can be drawn as ACE-loaded CDNS based gel has the potential to improve the transdermal bioavailability of aceclofenac against osteoarthritis with less adverse actions.