Soluble Active Pharmaceutical Ingredients Research Articles

Theoretical modeling and prediction of biorelevant solubility of poorly soluble pharmaceuticals

The solubility of active pharmaceutical ingredients (APIs) in biorelevant media is important fundamental data for API formulation design and contributes to better evaluation of in vivo dissolution kinetics. However, these data are mainly determined by experimental measurements, which is rather time and cost consuming. Therefore, it is essential to develop a novel theoretical strategy to describe and predict API solubility in biorelevant media. In this work, the solubilization effect of micelle and the effect of pH as well as ion components on the solubility of naproxen and indomethacin were determined experimentally. A micellar solubilization model and pH-dependent solubility model were proposed to model the effect of various micelles and pH (including buffer components) on API aqueous solubility, respectively. The combination of the two model successfully described the biorelevant solubility of APIs as function of temperature. The proposed strategy could provide insights into the mechanisms of micelle and different pH regulated by different buffer components on API solubility and could accurately describe the solubility of APIs in biorelevant media. This work is expected to provide theoretical guidance for API formulation development.

Adding a New Dimension to the Amorphous Solid Dispersion Phase Diagram: Studying Dissolution Kinetics of Crystalline Drugs in a Polymer Matrix Using Temperature Dependent XRPD and DSC

Hot-melt-extrusion (HME) is an enabling technology used for poorly soluble active pharmaceutical ingredients (APIs) to increase the bioavailability by embedding the drug in a water soluble and often amorphous carrier such as a polymer. Knowledge of the most critical factors impacting the dissolution rate of crystalline API in the polymer during manufacturing will provide useful insight for process improvement. In this study, crystalline APIs (Acetaminophen, APAP and Indomethacin, IMC) were analyzed in a polymeric matrix (Copovidone, PVP-VA64) via X-Ray Powder Diffraction (XRPD) and Differential Scanning Calorimetry (DSC) to follow the dissolution process under various conditions in a down-scaled static laboratory system. The combination of in-situ XRPD measurements and a kinetic model based on DSC data proved to be a suitable tool to investigate the dissolution process and can be applied to various APIs and polymers to avoid residual crystallinity and thermal degradation. Thus, the temperature-composition phase diagram in a thermodynamic equilibrium is augmented by the kinetic component as new dimension. The obtained findings set the foundation for investigating the dissolution kinetics and enable the transition from a static to a dynamic system.

Long-term stability of clopidogrel solid dispersions-Importance of in vitro dissolution test.

Formulation of solid dispersions (SDs), in which the drug substance is dissolved or dispersed inside a polymer matrix, is one of the modern approaches to increase the solubility and dissolution rate of poorly soluble active pharmaceutical ingredients (APIs), such as clopidogrel. In the form of a free base, clopidogrel is unstable under increased both high moisture and temperature, so it is most often used as its salt form, clopidogrel hydrogen sulfate (CHS).The aim of this study was the formulation, characterization, and long-term stability investigation of CHS solid dispersions, prepared with four different hydrophilic polymers (poloxamer 407, macrogol 6000, povidone, copovidone) in five API/polymer ratios (1:1, 1:2, 1:3, 1:5, 1:9). SDs were prepared by the solvent evaporation method, employing ethanol (96% v/v) as a solvent. Initial results of the in vitro dissolution test showed an increase in the amount of dissolved CHS from all prepared SD samples compared to pure CHS, corresponding physical mixtures (PMs), and commercial tablets. SDs, prepared with poloxamer 407, macrogol 6000, and copovidone, at CHS/polymer ratios 1:5 and 1:9, notably increased the amount of dissolved CHS (> 80%, after 60 min), thus they were selected for further characterization. To assess the SDs long-term stability, in vitro dissolution studies, clopidogrel content determination, differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FT-IR) were performed initially and after 12 months of long-term stability studies under controlled conditions (25°C, 60% RH) meeting the ICH guideline Q1A (R2) requirements. The clopidogrel content in the selected samples was very similar at the beginning (96.13% to 99.93%) and at the end (95.98% to 99.86%) of the conducted test. DSC curves and FT-IR spectra of all SD samples after 12 months of stability study, showed the absence of CHS crystallization, which is an indication of good stability. However, the in vitro dissolution test showed a considerable reduction in CHS released from SDs with macrogol 6000. The amount of dissolved CHS from SDs with macrogol 6000 was initially 94.02% and 92.01%, and after 12 months of stability study, only 65.13% and 49.62%. In contrast, the amount of dissolved CHS from SDs prepared with poloxamer 407 and copovidone was very similar after 12 months of the stability study compared to the initial values. Results obtained indicated the great importance of the in vitro dissolution test in determining the long-term stability and quality of SDs.

A Brief Review on Ophthalmic Suspension for Covid-19 Infection

Delivering a drug to eye has been a major challenge to pharmacologists and drug delivery scientists (Gaudana et al 2010). It is due to its complex structure and unique anatomy and physiology. This results only small portion of drug reaches to the site of action. The eye contains two main chambers, anterior chamber and posterior chamber (Chen et al., 2018). As the renewal time of tear fluid is less than 5 minutes (Mishima, Gusset et al., 1996) ophthalmic drug washout very quickly from anterior portion of cornea. To prevail over with this issue various formulations strategies have been investigated to increase ocular drug retention. In ophthalmic formulations the suspension is better option for incorporating poorly soluble active pharmaceutical ingredients. As ophthalmic suspension improvise drug delivery by enhancing retention time of drug, thereby increasing the bioavailability of the drug. In this review we will discuss about the important parameters that are considered in the formulation of ophthalmic suspension.

Acetic Acid as Processing Aid Dramatically Improves Organic Solvent Solubility of Weakly Basic Drugs for Spray Dried Dispersion Manufacture.

Many active pharmaceutical ingredients (APIs) in the pharmaceutical pipeline require bioavailability enhancing formulations due to very low aqueous solubility. Although spray dried dispersions (SDDs) have demonstrated broad utility in enhancing the bioavailability of such APIs by trapping them in a high-energy amorphous form, many new chemical entities (NCEs) are poorly soluble not just in water, but in preferred organic spray drying solvents, e.g., methanol (MeOH) and acetone. Spraying poorly solvent soluble APIs from dilute solutions leads to low process throughput and small particles that challenge downstream processing. For APIs with basic pKa values, spray solvent solubility can be dramatically increased by using an acid to ionize the API. Specifically, we show that acetic acid can increase API solubility in MeOH:H2O by 10-fold for a weakly basic drug, gefitinib (GEF, pKa 7.2), by ionizing GEF to form the transient acetate salt. The acetic acid is removed during drying, resulting in a SDD of the original GEF free base having performance similar to SDDs sprayed from solvents without acetic acid. The increase in solvent solubility enables large scale manufacturing for these challenging APIs by significantly increasing the throughput and reducing the amount of solvent required.

Solids Turn into Liquids-Liquid Eutectic Systems of Pharmaceutics to Improve Drug Solubility.

The low solubility of active pharmaceutical ingredients (APIs) is a problem in pharmaceutical development. Several methodologies can be used to improve API solubility, including the use of eutectic systems in which one of the constituents is the API. This class of compounds is commonly called Therapeutic Deep Eutectic Systems (THEDES). THEDES has been gaining attention due to their properties such as non-toxicity, biodegradability, and being non-expensive and easy to prepare. Since the knowledge of the solid liquid diagram of the mixture and the ideal eutectic point is necessary to ascertain if a mixture is a deep eutectic or just a eutectic mixture that is liquid at ambient temperature, the systems studied in this work are called Therapeutic Liquid Eutectic Systems (THELES). Therefore, the strategy proposed in this work is to improve the solubility of chlorpropamide and tolbutamide by preparing THELES. Both APIs are sulfonylurea compounds used for the treatment of type 2 diabetes mellitus and have low solubility in water. To prepare the THELES, several coformers were tested, namely, tromethamine, L(+)-arginine, L-tryptophan, citric acid, malic acid, ascorbic acid, and p-aminobenzoic acid, in molar ratios of 1:1 and 1:2. To improve viscosity, water was added in different molar ratios to all systems. THELES were characterized by mid-infrared spectroscopy (MIR), and differential scanning calorimetry. Their viscosity, solubility, and permeability were also determined. Their stability at room temperature and 40 °C was accessed by MIR. Cytocompatibility was performed by metabolic activity and cell lysis evaluation, according to ISO10993-5:2009, and compared with the crystalline APIs. THELES with TRIS were successfully synthesized for both APIs. Results showed an increased solubility without a decrease in the permeability of the APIs in the THELES when compared with the pure APIs. The THELES were also considered stable for 8 weeks at ambient temperature. The cells studied showed that the THELES were not toxic for the cell lines used.

Faster to First-time-in-Human: Prediction of the liquid solid ratio for continuous wet granulation

In early development, when active pharmaceutical ingredient (API) is in short supply, it would be beneficial to reduce the number of experiments by predicting a suitable L/S ratio before starting the product development. The aim of the study was to decrease development time and the amount of API needed for the process development of high drug load formulations for continuous twin-screw wet granulation (TSWG). Mixer torque rheometry was used as a pre-formulation tool to predict the suitable L/S ratios for granulation experiments. Three different values that were based on the MTR curves, were determined and assessed for their ability to predict the suitable L/S ratio for TSWG. Three APIs (allopurinol, paracetamol and metformin HCl) were used as model substances in high drug load formulations containing 60% drug substance. The MCC-mannitol ratio was varied to assess the optimal composition for the high-dose formulations. The API solubility affected the mixer torque rheometer (MTR) curves and the optimum L/S ratio for TSWG. The highly soluble metformin needed a much lower L/S ratio compared with allopurinol and paracetamol. A design space was determined for each API based on granule flowability and tablet tensile strength. The flowability of the granules and tensile strength of the tablets improved with an increasing L/S ratio. The MCC-mannitol filler ratio had a significant effect on tabletability for paracetamol and metformin, and these APIs having poor compaction properties needed higher MCC ratios to achieve the 2 MPa limit. The MCC-mannitol ratio had no effect on the granule flow properties. Instead, API properties had the largest influence on both granule flow properties and tensile strength. Based on this study, both the L/S ratio and MCC-mannitol ratio are crucial in controlling the critical quality attributes in high drug load formulations processed by TSWG. The optimum flow and tablet mechanical properties were achieved when using 75:25 MCC-mannitol ratio. Both start of the slope and 2/3 of the L/S ratio at the maximum torque in MTR provided a solid guideline to aim for in a TSWG experiment.

Solubility and dissolution rate of progesterone cocrystals using 4-fluorobenzoic acid and 2-hydroxy-6-naphthoic acid as coformers

The objective of our study was to improve the solubility and consequently enhance the oral bioavailability of progesterone, an endogenous steroid with poor water solubility, by synthesizing cocrystals. Progesterone cocrystals with pharmaceutically acceptable conformers, namely, 4-fluorobenzoic acid and 2-hydroxy-6-naphthoic acid, in a stoichiometric ratio of 1:4 and 1:2, respectively, were synthesized using solution crystallization technology. The cocrystals were characterized using single-crystal X-ray diffraction, powder X-ray diffraction, Fourier-transform infrared spectroscopy, differential scanning calorimetry, and thermogravimetry. Results from the solubility and dissolution experiments indicated that the solubility of both progesterone cocrystals in water and dissolution rate in 0.1 M HCl solution (pH = 1) could enhance the aqueous solubility of progesterone 1.93 and 1.12 times, respectively. Therefore, the formulation of pharmaceutical cocrystals is a potentially viable and effective approach to improve the solubility of active pharmaceutical ingredients that are poorly water soluble.

Hydrogel Microparticle-Templated Anti-Solvent Crystallization of Small-Molecule Drugs.

Conventional formulation strategies for hydrophobic small-molecule drug products frequently include mechanical milling to decrease active pharmaceutical ingredient (API) crystal size and subsequent granulation processes to produce an easily handled powder. A hydrogel-templated anti-solvent crystallization method is presented for the facile fabrication of microparticles containing dispersed nanocrystals of poorly soluble API. Direct crystallization within a porous hydrogel particle template yields core-shell structures in which the hydrogel core containing API nanocrystals is encased by a crystalline API shell. The process of controllable loading (up to 64% w/w) is demonstrated, and tailored dissolution profiles are achieved by simply altering the template particle size. API release is well described by a shrinking core model. Overall, the approach is a simple, scalable and potentially generalizable method that enables novel means of independently controlling both API crystallization and excipient characteristics, offering a "designer" drug particle system.

Formulation and Characterization of SNEDDS of Dayak Onion Extract with Comparative Variations of Surfactants, Co-Surfactants, and Palm Oil

Self-Nanoemulsifying Drug Delivery System (SNEDDS) is a thermodynamically stable drug administration unit with the capacity to increase the solubility of active pharmaceutical ingredients (API) and bioavailability. In addition, dayak onion extract is an active ingredient developed to increase the effectiveness of therapy. The aims to formulate, characterize, and investigate stability. Moreover, the HLB approach was used to formulate SNEDDS from dayak onion extract, with a component ratio of palm oil, a combination of surfactants (hydrophilic Tween 80, Tween 20) and lipophilic (Span 20 and Transcutol) and PEG 400 as co-surfactants. A total of sixty formulas were used, with an HLB range of 11-15 and a ratio of 1:8:1, 1:7:2, and 2:7:1, followed by evaluating product characteristics. Furthermore, two formulas were selected, including F13 (HLB 13) and F34 (HLB 14), at ratios 1:8:1 and 1:7:2. The results showed particle size ranging from 10-200 nm, percent transmittance of <90%, while the viscosity and pH values were stable at various dilutions. The evaluation for thermodynamics indicates an unstable preparation. Therefore, the SNEDDS formula of dayak onion extract using long-chain triglycerides (palm oil) was ineffective.

Enteric and hydrophilic polymers enhance dissolution and absorption of poorly soluble acidic drugs based on micro-environmental pH-modifying solid dispersion

The oral bioavailability of poorly water-soluble active pharmaceutical ingredient (API) is often inadequate for the desired therapeutic effect. Micro-environmental pH-modifying solid dispersion (micro pHm SD) is an effective method for enhancing the dissolution of pH-dependent soluble APIs. However, erratic bioavailability of these drugs was often found when the micro pHm SD of the drugs was orally administrated and passed through the gastrointestinal tract. Because the added alkalizer in micro pHm SD could be neutralized by the acid in the stomach, as a result not enough alkalizer is left to form alkaline micro-environment around the drug in the intestine, leading to poor dissolution and bioavailability of API. Enteric polymers are applicable materials for site-specific drug delivery that are insoluble in gastric tract but soluble in the intestine targeted for drug release. In this study, a poorly water-soluble model drug, toltrazuril (TOL), was prepared as enteric micro pHm SD with enteric, hydrophilic polymers and alkalizer. The surface of enteric micro pHm SD tablets staining and alkalizer protection test in the acid dissolution medium qualitatively and quantitatively confirmed the protective effects of the enteric polymer on the alkalizer. Dissolution studies revealed that the drug release from the enteric micro pHm SDs was improved significantly compared with micro pHm SD with no enteric polymer. The pH-dependent solubility of enteric polymer had effects on the dissolution of APIs from the SDs in neutral medium. Enteric micro pHm SDs with higher proportion of enteric polymer showed higher Cmax and dissolution rate of TOL. The physicochemical characterization and the molecular interaction between drug and matrix were analyzed by electron microscopy (SEM), differential scanning calorimetry (DSC), and fourier transform infrared spectroscopy (FTIR), finding that the formation of hydrogen bonds between TOL and matrix was helpful to promote dissolution of TOL. Ca(OH)2-TOL-PVPk30-HPMCAS 8: 8: 18: 6 was determined as the most optimal enteric micro pHm SD, which significantly improved the bioavailability of TOL and its active metabolism (TOLSO, TOLSO2) in pharmacokinetic study and could effectively reduce the irritation of the gastrointestinal mucosa caused by the alkalizer Ca(OH)2 when the SD was orally administrated to rabbits. The present study demonstrates that formulating APIs with poor water solubility as enteric micro pHm SD is an effective method for protecting the alkalizer in SD and improving the dissolution of APIs and the bioavailability following oral administration.

Characterization of excipients to improve pharmaceutical properties of sirolimus in the supercritical anti-solvent fluidized process

Enhanced drug release and bioavailability of poorly soluble active pharmaceutical ingredient (API) can be achieved via a fluidized bed coating integrated with supercritical anti-solvent (SAS-FB) – a process of precipitating drug particles onto carrier granules. However, in the absence of excipients, SAS-FB often results in crystalline of the API on the surface of carriers, limiting the improvement of pharmaceutical properties. Co-processing with excipients is considered an effective approach to improve drug release in the SAS-FB process. Our study used sirolimus, an immune suppressive agent, as the model API to characterize excipients for their effect on pharmaceutical properties in the SAS-FB process. We show that co-precipitation of excipients and sirolumus impacts on carrier specific surface area and drug yield. Among the tested excipients, formulation containing polyvinylpyrrolidone K30 achieved the highest drug yield. Importantly, compared with Rapamune® tablet, our optimized formulation displayed a superior in vivo oral bioavailability by 3.05-fold in Sprague-Dawley rats and 3.99-fold in beagle dogs. A series of characterization of the processed API was performed to understand the mechanism by which excipients contributed to drug dissolution properties. Our study provides a useful guidance for the use of excipients in the SAS-FB technology to improve pharmaceutical properties of sirolimus and other poorly soluble drugs.

Recent Advances in Pharmaceutical Cocrystals: From Bench to Market.

The pharmacokinetics profile of active pharmaceutical ingredients (APIs) in the solid pharmaceutical dosage forms is largely dependent on the solid-state characteristics of the chemicals to understand the physicochemical properties by particle size, size distribution, surface area, solubility, stability, porosity, thermal properties, etc. The formation of salts, solvates, and polymorphs are the conventional strategies for altering the solid characteristics of pharmaceutical compounds, but they have their own limitations. Cocrystallization approach was established as an alternative method for tuning the solubility, permeability, and processability of APIs by introducing another compatible molecule/s into the crystal structure without affecting its therapeutic efficacy to successfully develop the formulation with the desired pharmacokinetic profile. In the present review, we have grossly focused on cocrystallization, particularly at different stages of development, from design to production. Furthermore, we have also discussed regulatory guidelines for pharmaceutical industries and challenges associated with the design, development and production of pharmaceutical cocrystals with commercially available cocrystal-based products.

Formulasi, Karakterisasi, Dan Evaluasi Drops Liquid Self Nano-Emulsifying Drug Delivery System (SNEDDS) Astaxanthin

SNEDDS are isotropic mixtures of oil, surfactant, and cosurfactant that produce spontaneous nanoemulsions once they make contact with gastric juices in order to increase the solubility of active pharmaceutical ingredients. One of the active pharmaceutical ingredients with low solubility is Astaxanthin. This research aims at formulating, characterizing, and evaluating SNEDDS containing Astaxanthin in the form of droplets. This research is a laboratory experiment. SNEDDS containing Astaxanthin droplets are made in 3 formulas using the ratio of surfactants and co-surfactants which are characterized to produce F1, F2, and F3 transmittance values of 91%, 90%, and 95%, respectively. Furthermore, the F1 particle size value of 183.75 nm obtains a PDI value of 0.272, the F2 particle sizevalue of 195.25 nm obtains a PDI value of 0.341, and the F3 particle size value of 105.75 nm obtains a PDI value of 0.392. This signifies that the absorption efficiency of F1, F2, and F3 are 94.62%, 94.35%, and 95.57%, respectively. The evaluation reveals the insignificant changes in the emulsion viscosities of SNEDDS containing Astaxanthin liquid drop after having received a stability test for 28 days using Paired T. Test data analysis (p0.05). The research findings show that the F3 of 72% surfactant and 18% co-surfactant concentrations are the best formula in producing SNEDDS. It concludes thar the higher the surfactant concentration produced, the greater the ability to, oil droplets resulting in obtaining small partidles and high absorption efficiency.

Applications of Deep Eutectic Solvents Related to Health, Synthesis, and Extraction of Natural Based Chemicals

Deep eutectic solvents are liquid mixtures of solid components at room temperature, which present exceptional properties: high solvent capacity, high biodegradation, low volatile organic compound character, and relatively low toxicity. Furthermore, there are an important number of DES described, formed by different components and ratios, and thus, the studied applications are also numerous. In this review, we focused on the applications related to health. One of the most promising applications of DES is the development of oral liquid formulations of poorly soluble active pharmaceutical ingredients, although it currently remains at an early stage. We have analyzed the potential and limitations of DES with this regard. Furthermore, DES have been used as synthesis media. In this work, we revised the use of DES to obtain bioactive natural products via synthesis or extraction process. Finally, the usefulness of DES in other interesting applications for promoting health has been also examined: this is the case of genomics studies, nano-carriers for the encapsulation of anticancer drugs or stabilization of samples for medical purposes.

Experimental and Theoretical Screening for Green Solvents Improving Sulfamethizole Solubility.

Solubility enhancement of poorly soluble active pharmaceutical ingredients is of crucial importance for drug development and processing. Extensive experimental screening is limited due to the vast number of potential solvent combinations. Hence, theoretical models can offer valuable hints for guiding experiments aimed at providing solubility data. In this paper, we explore the possibility of applying quantum-chemistry-derived molecular descriptors, adequate for development of an ensemble of neural networks model (ENNM), for solubility computations of sulfamethizole (SMT) in neat and aqueous binary solvent mixtures. The machine learning procedure utilized information encoded in σ-potential profiles computed using the COSMO-RS approach. The resulting nonlinear model is accurate in backcomputing SMT solubility and allowed for extensive screening of green solvents. Since the experimental characteristics of SMT solubility are limited, the data pool was extended by new solubility measurements in water, five neat organic solvents (acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, and methanol), and their aqueous binary mixtures at 298.15, 303.15, 308.15, and 313.15 K. Experimentally determined order of decreasing SMT solubility in neat solvents is the following: N,N-dimethylformamide > dimethyl sulfoxide > methanol > acetonitrile > 1,4dioxane >> water, in all studied temperatures. Similar trends are observed for aqueous binary mixtures. Since N,N-dimethylformamide is not considered as a green solvent, the more acceptable replacers were searched for using the developed model. This step led to the conclusion that 4-formylmorpholine is a real alternative to N,N-dimethylformamide, fulfilling all requirements of both high dissolution potential and environmental friendliness.

Solvent-Assisted Hot Melt Extrusion of a Thermally Labile, High Melting Point Compound

Molecular dispersions are a highly effective method of increasing bioavailability for a poorly soluble active pharmaceutical ingredient (API) and can be prepared on a large scale by hot melt extrusion (HME). Processing thermally labile active pharmaceutical ingredients (APIs) via HME is generally more difficult, with operating temperatures limited to below that of the API melting point. API melting is considered essential to facilitate the formation of a fully homogeneous amorphous system. Processing below the melting point renders the system much more susceptible to residual crystalline content; hence, HME is not suitable for APIs which degrade upon melting. In the following work, meloxicam (MEL) was used as a model API, possessing properties of high melting temperature and thermal lability. In this proof of concept work, a modified HME method, termed solvent-assisted HME, was used to overcome this issue and prepare an amorphous solid dispersion using HME, wherein a solvent was incorporated in the formulation blend during extrusion and removed post-processing. Formulations containing 10%wt meloxicam (MEL) and 90%wt polyvinylpyrrolidone vinyl acetate (PVPVA) copolymer were extruded using a twin-screw extruder at temperatures below the melting point of MEL. Dimethylformamide (DMF) solvent was added directly into the extruder barrel through a liquid addition port, resulting in extrudate products having a higher conversion of API to the amorphous form. The incorporation of solvent allowed a significant reduction in processing temperatures due to its increased mobility, while also driving the conversion of the API to its amorphous form. The solvent was successfully reduced through a secondary drying step using a vacuum oven. This advancement has demonstrated the potential for thermally labile APIs to be processed via HME expanding the applications of this technology.

The role of excipients of trometamolum and meglumine in the formation of biopharmaceutical properties of medicinal products of various pharmacites

At the present stage of development of the pharmaceutical industry, the use of many functional excipients (DopR), which are important components of pharmaceutical formulations, becomes relevant. DopR is one of the most influential biopharmaceutical factors on the therapeutic efficacy of drugs, increasing the therapeutic effect and safety of active pharmaceutical ingredients (APIs) through the formation of optimal compounds and appropriate dosage forms by chemical modification of the molecule responsible for pharmacological activity.
 The purpose of the work is to analyze the literature on determining the role of excipients of trometamol and meglumine as biopharmaceutical factors in drugs of different pharmacotherapeutic groups; summarize and systematize data on their impact on the bioavailability of finished drugs.
 The objects of the study are excipients trometamоlum (TНAM) and meglumine (MGA) in the composition of drugs of different pharmacotherapeutic groups. Methods of a systematic approach, bibliographic, information retrieval, generalization and analysis were used in the research.
 A systematic study of the composition of drugs of the State Register of Medicinal Products (January 2021) showed that chemically modified drugs are supplied to the pharmaceutical market not only by domestic manufacturers, but also by pharmaceutical companies from 16 countries. The general nomenclature of drugs makes 82 trade names, from them 66% – with TMM and 34% – with MGA.
 A significant number of chemically modified insoluble and sparingly soluble APIs of different pharmacotherapeutic groups indicates a significant role of TMM and IGA in the development of new effective drugs.
 Thus, organic aminoproton acceptors: trometamol and meglumine – many functional excipients that increase the activity of active molecules, their release from dosage forms, stimulate the pharmacotherapeutic effect of drugs aimed at activating the protective forces (sanogenesis) and compensatory mechanisms of the body and thus, improve the pharmacological properties of drugs, reduce the risk of adverse reactions.

Cellulose derivatives as effective recrystallization inhibitor for ternary ritonavir solid dispersions: In vitro-in vivo evaluation

Amorphous solid dispersions (ASDs) are regarded as one of the most promising techniques for poorly-soluble active pharmaceutical ingredients (API). However, the thermodynamic instability of ASDs at supersaturated state makes them easy to recrystallize in aqueous media. In this study, ritonavir (RTV) was selected as a model drug for evaluating the solubility enhancement and recrystallization inhibition effect of various cellulose derivatives and the combinations of them with typical surfactants. Combination of HPMCAS-HF/SLS was filtrated for preparing ternary RTV solid dispersions (RTV SD) via solvent evaporation method. RTV SD exhibited enhanced dissolution manner, while the oral bioavailability of RTV SD was equivalent with the Reference Standard Norvir® but increased significantly compared to the ternary physical mixture. Thus, the ternary SD system might be promisingly employed as efficient drug delivery system for RTV, while the HPMCAS-HF/SLS combination could be recommended as effective excipient for fabricating steady solid dispersions loading poorly soluble API.

Characterization of nanoparticles made of ethyl cellulose and stabilizing lipids: Mode of manufacturing, size modulation, and study of their effect on keratinocytes

We have developed an ethyl cellulose-based nanoparticulate system for encapsulation of sparingly soluble active pharmaceutical ingredients. Cannabidiol (CBD) and curcumin (CUR) were selected as model active ingredients. Using the nanoprecipitation method, nanoparticles ranged between 150 nm and 250 nm were obtained with an entrapment efficiency of >80%. It has been shown that incorporation of stabilizing lipids significantly reduced aggregation, increased the yield and the active ingredient-to-polymer ratio. In this study, we have explored the influence of process parameters on the extent of new particle core formation: chemical properties of the active ingredients, polymer concentrations, non-solvent addition rate, and the volume of the organic solvent for nanoparticle size control. The relationship between the particle radius [R] and the polymer concentration [Pol] was defined by R ∝ [Pol]n when n < ⅓. The extent of polymer supersaturation was related to the value of n, when the high polymer supersaturation increased the formation rate of new particle cores while decreasing polymer layering on the existing cores and the nanoparticles size. The obtained nanoparticles have shown low toxicity in keratinocytes, however, higher loadings of CUR or CBD resulted in increased toxicity. The nanoparticles effectively internalized into keratinocytes, implying their applicability for dermal delivery.