Mixtures Of Active Pharmaceutical Ingredients Research Articles

Binary Mixtures of Meloxicam and L-Tartaric Acid for Oral Bioavailability Modulation of Pharmaceutical Dosage Forms.

Binary mixtures of active pharmaceutical ingredients (API) are researched to improve the oral bioavailability of pharmaceutical dosage forms. The purpose of this study was to obtain mixtures of meloxicam and L-tartaric acid because tartaric acid improves intestinal absorption and meloxicam is more soluble in a weakly basic environment. The mixtures in the 0-1 molar fraction range, obtained from solvent-assisted mechanosynthesis, were investigated by differential scanning calorimetry (DSC), Fourier Transform Infrared (FTIR) spectroscopy, Fourier Transform Raman spectroscopy (FT-Raman), X-ray powder diffraction (XRD) and solubility tests. The physicochemical characteristics of the compounds obtained from DSC data reveal, for the first time, the formation of a co-crystal at meloxicam molar fraction of 0.5. FTIR spectroscopy data show the existence of hydrogen bonds between the co-crystal components meloxicam and L-tartaric acid. FT-Raman spectroscopy was used complementary with FT-IR spectroscopy to analyze the pure APIs and their mixtures, to emphasize the appearance/disappearance and the shifts of the position/intensity of vibrational bands, following the formation of hydrogen-bonded structures or van der Waals interactions, and to especially monitor the crystal lattice vibrations below 400 cm-1. The experimental results obtained by X-ray powder diffraction confirmed the formation of the co-crystal by the loss and, respectively, the apparition of peaks from the single components in the co-crystal diffractogram. The solubility tests showed that the co-crystal product has a lower aqueous solubility due to the acidic character of the other component, tartaric acid. However, when the solubility tests were performed in buffer solution of pH 7.4, the solubility of meloxicam from the co-crystal mixture was increased by 57% compared to that of pure meloxicam. In conclusion, the studied API mixtures may be considered potential biomaterials for improved drug release molecular solids.

Study the solubility of pharmaceutical ingredients and their eutectic mixtures: An in-depth density functional theory and molecular dynamics simulations approaches

Solubility is a major concern for many active pharmaceutical ingredients (APIs) and drugs. Owing to their better solubility, biodegradability and low toxicity of APIs and drugs, eutectic mixtures are emerging as the system to enhance their solubility with no loss of biological activity. In the present work, authors have taken camizestrant, deucravacitinib, and iclepertin as the active pharmaceutical ingredients (API) because they have poor solubility in water. Authors have designed eutectic mixtures (EMs) of the selected APIs with the amino acids (aspartic acid, lysine, phenylalanine, and proline) and studied for their physiochemical properties in default and water using density functional theory calculations, performed by Gaussian. The solubility of the APIs, amino acids and the designed eutectic mixtures of APIs have been determined and discussed using the dipole moment. The results showed that the solubility of the designed eutectic mixtures have better aqueous solubility than the APIs alone. Further, molecular dynamics (MD) simulations were done for APIs and EMs to study their stability and interactions.

Development of affinity polymeric particles for the removal of 4-dimethylaminopyridine (DMAP) from active pharmaceutical ingredient crude streams using a green technology

Polymeric particles with affinity for 4-dimethylaminipyridine (DMAP) were developed by molecular imprinting using supercritical carbon dioxide (scCO2) technology, for cleanup of this potentially genotoxic impurity from crude mixtures of Active Pharmaceutical Ingredients (APIs). DMAP-molecularly imprinted polymer (DMAP-MIP) and the respective control, the non-molecularly imprinted polymer (NIP) were produced by free radical polymerization using methacrylic acid as monomer, ethylene glycol dimethacrylate as crosslinker and AIBN as free-radical initiator in scCO2. The materials were obtained in high yield and were characterized chemically, physically and morphologically. Their extraction efficiency was evaluated by dynamic binding experiments using two solutions: i) a solution containing 104 ppm DMAP solution; ii) model pharmaceutical mixture containing 104 ppm of DMAP and 1018 ppm of Mometasone furoate (API). Particles were able to remove 18.3 µmol DMAP/g polymer from a 104 ppm DMAP solution (i) and 1004.6 µmol DMAP/g API (ii). In addition, high recoveries of both DMAP and API were obtained, above 99%.

Structure and energetics of intermolecular association in two lurasidone co-amorphous drug systems

The use of amorphous phases has been proposed as one of the alternatives for drug formulations of low solubility active pharmaceutical ingredients (API). To overcome stability problems of these metastable phases, co-amorphous mixtures of API with safe small molecule co-formers are being investigated. Therefore, it is of great importance to study the factors that control the supramolecular association of drug substance with the co-formers, despite lack of long-range order in these systems creating some experimental and computational challenges. This work aims to apply various computational chemistry methods to the study of co-amorphous drug systems, namely the local structural and intermolecular interactions responsible for the intimate drug–co-former association that prevents relaxation to the crystalline state. The subjects of this study are two co-amorphous systems, recently proposed and studied experimentally, that include the drug lurasidone with two different co-formers, saccharin and cysteine. First, the conformational landscape of lurasidone is explored by random search molecular mechanics to provide a varied set of initial conformations. Then, these conformations and those extracted from the available X-ray diffraction crystal structures of the three component substances are subject to geometry optimization by a DFT method (B3LYP/def2-SVP), including corrections for dispersion. The same optimization procedure is applied to homodimers extracted from the crystal structures, and to heterodimers built using the evidence for the manner of aggregation provided by the published experimental studies. The intermolecular association is further explored with Natural Bond Orbital (NBO) and Non-Covalent Interaction (NCI) analyses of the dimers, to better understand the electronic structure of the supramolecular drug–co-former entities and compare how they interact. It is concluded that faster, more approximate, methods were useful to deal with large and conformationally flexible drug molecules that are typical amorphous phase formers, and that the more rigorous quantum mechanical methods are necessary to rationalize and evaluate the molecular interactions in co-amorphous systems. The NBO analysis indicated that lurasidone has stronger hydrogen bonding with cysteine than with saccharin.

Raman imaging of amorphous-amorphous phase separation in small molecule co-amorphous systems

Many new active pharmaceutical ingredients (API) undergoing development have low permeabilities or low aqueous solubilities. However, the amorphous state is usually more soluble than its crystalline counterpart. The amorphous state has a higher Gibb’s free energy, which can improve the apparent solubility but decrease the stability since the amorphous state tends to transform to the more stable crystalline form. Before recrystallization, a co-amorphous binary mixture’s ingredients have to undergo a phase separation. The aim of this study was to obtain a better understanding of the amorphous-amorphous phase separation in co-amorphous binary mixtures and test the suitability of imaging Raman spectroscopy for detecting this phenomenon. To study the phase separation, we prepared three different 50:50 mass ratio binary mixtures of APIs: paracetamol-terfenadine, (PAR-TRF), paracetamol-indomethacin (PAR-IMC) and terfenadine-indomethacin (TRF-IMC). The binary mixtures were amorphized with melt-quenching and stored above their glass transition temperature (Tg) to monitor their phase separation. Thermal degradation was determined with a high performance liquid chromatography (HPLC) method to ensure that melt-quenching did not cause any thermal degradation of the molecules. Thermodynamic attributes (crystallization tendency, melting point (Tm) and Tg) were measured with differential scanning calorimetry (DSC) to ensure that the co-amorphous systems transformed to the amorphous state and remained amorphous after cooling and reheating. Phase separation was studied from the surface and cross-section (CS) with Raman imaging to examine if it occurred more on the surface than in the bulk. The Raman spectra were analyzed with principal component analysis (PCA) and Contour plots were produced from the PCA-score values to visualize concentration differences in the mixtures. The results showed that API vs API concentrations increased as a function of time in both surface and CS images before crystallization. This suggests that Raman imaging is a suitable technique to detect the phase separation phenomena in small molecule co-amorphous binary mixtures.

The pharmacotechnological studies on the development of the plant raw material for the treatment of cardiovascular diseases

Cardiovascular diseases are the most frequent cause of death in the world. Since ancient times, people used medicinal plants to cure a variety of ailments. Herbal treatment has not lost its relevance for today. The medicinal plant raw material used in scientific and folk medicine to improve the state of the cardiovascular system includes hawthorn fruits, mint leaves, lemon balm leaves and Greek valerian roots.Aim. To conduct the pharmacotechnological studies on the development of the composition and technology for the oral solid dosage form intended for prevention and treatment of cardiovascular diseases.Materials and methods. Powders of the plant raw material were studied by the following parameters: bulk density, flowability and moisture content. The microscopic analysis of powder particles was performed. The pharmacotechnological parameters of the model mixtures of active pharmaceutical ingredients with addition of excipients – flowability, compressibility and disintegration – were determined.Results and discussion. The microscopic analysis has shown that the mixture of the powdered plant raw material is a polydisperse system with particles that differ in shape. Based on this analysis it is possible to predict the unsatisfactory flowability of the mixture and, therefore, the necessity for the inclusion of excipients. To determine the composition of excipients in the preparation being developed the pharmacotechnological parameters of the model mixtures of the plant powders with the addition of microcrystalline cellulose, lactose (FlawLac and CapsuLac) and corn starch were studied. The amount of each component was determined experimentally. To provide flowability the method of wet granulation was chosen.Conclusions. The study of physicochemical and pharmacotechnological properties of powders of the medicinal plant raw material has shown poor flow characteristics. In order to improve the technological properties of the mixture such excipients as microcrystalline cellulose, FlawLac and CapsuLac lactose, aerosil and calcium stearate have been added. The use of the wet granulation method has been substantiated to increase the flowability of the mass. As a moisturizer 5 % starch paste has been chosen. The parameters of drying of wet granules have been studied, and the temperature (55 ± 5) °C has been set.

Solubility of pharmaceutical ingredients in triglycerides

Lipid-based drug delivery systems (LBDDS) are highly relevant as pharmaceutical formulations significantly enhancing the bioavailability of active pharmaceutical ingredients (APIs). These formulations often are complex mixtures of APIs, various lipids, and other excipients (e.g. surfactants). In their simplest form, LBDDS contain one API being dissolved in a pure lipid, which often is a triglyceride (TG). In this work, solubilities of the APIs indomethacin, ibuprofen, and fenofibrate in pure TGs of different chain lengths (C chain 8–18) and degree of saturation were investigated. Solubilities of APIs in TGs were measured via differential scanning calorimetry, hot-stage microscopy, high-performance liquid chromatography, and Raman spectroscopy. The influence of fatty-acid chain length and degree of saturation on the API solubility in the TGs was investigated. APIs showed a higher solubility in saturated (wIBU = 10.5 wt% at 25 °C in tricaprylin) TGs compared to unsaturated ones (wIBU = 4.0 wt% at 25 °C in triolein). The fatty-acid chain length of TGs only slightly affects the solubility of ibuprofen and fenofibrate, but strongly influences the eutectic temperature of the API/TG mixtures.API solubilities in TGs and TG mixtures (mixtures of tricaprylin and tricaprin) were successfully modeled using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) accounting for the intermolecular API/TG interactions providing a deep understanding of the energetic and structural impact of the TGs on API solubility.

Safety of Pharmaceutical Excipients and Regulatory Issues

Background:Pharmaceutical excipients are critical in the formulation of any dosage form. Not many additives employed in the drug product manufacture have properties, which meet the desired qualities that the finished product must have. Therefore, it is mandatory to mix the drug substance with other substances to overcome the deficiencies. As a result, almost all pharmaceutical products are mixtures of active pharmaceutical ingredient and additives. So, there is a compelling need of these substances and normally they occupy the major part of any drug product. Excipients are of different chemical categories that have varying physicochemical properties like solubility, miscibility and the nature and source of these materials vary. With growing number of pharmaceutical excipients and polymers, the question of evaluating their toxicity is becoming a complex issue. Many polymers and novel excipients are now available in the market and with their diverse chemical nature and different sources and presence of impurities and their adverse effects will further complicate the safety profiling of these excipients.Conclusion:This review article will discuss the unwanted biological activities of some commonly used excipients and issues of the supply of the pharmaceutical excipients that need to be highly regulated and monitored to ensure availability of quality and pure excipient compounds.

The choice of intense sweetener in the composition of medicated chewing gum under development

Considering the simplicity and ease of use, in recent years, more and more attention deserves medicated chewing gum (MCG), which plays the role of oral drug delivery system. Since this product remains in the oral cavity for a longer time than other oral medicines, the taste is one of the important features of the MCG. It is known, that one of the ways to correct and mask the taste of medicines is the addition of intense sweeteners, which not only affect the taste characteristics of the ready product, but also can influence the physic-chemical and technological properties of the active components.
 The aim of this work was the selection of the optimal intensive sweetener in the developed dental MCG with lysozyme hydrochloride and ascorbic acid.
 As natural flavourers, we studied natural and synthetic intensive sweeteners: potassium acesulfame, aspartame, sodium cyclamate, sodium saccharin, stevia and sucralose. The choice of flavouring agents was carried out using organoleptic methods for evaluating the taste with the help of numerical indexes by A. I. Tentsova and use of alphabetic and numerical indexes by I. A. Yegorov, and also by studying the crystallographic properties of intense sweeteners and their mixtures with active pharmaceutical ingredients.
 According to the obtained results, all compositions, except for the sample with sodium saccharin, had a corrective property and had a similar sweet-sour taste. However, not all of them had a long sweet aftertaste, which is very important for this dosage form. The highest numerical indices were samples of MCG with sodium cyclamate, stevia and sucralose. By conducting a microscopic analysis of mixtures of active pharmaceutical ingredients with the investigated intense sweeteners were predicted possible methods of obtaining the developed solid dosage form – the method of direct compression or the use of preliminary granulation. Taking into account the complex of the obtained results, sucralose has the best correcting and physic-chemical characteristics of all the investigated intense sweeteners.

1H NMR Relaxation Study to Evaluate the Crystalline State of Active Pharmaceutical Ingredients Containing Solid Dosage Forms Using Time Domain NMR

The aim of this study was to demonstrate the usefulness of the time domain nuclear magnetic resonance (TD-NMR) method to characterize the crystalline state of active pharmaceutical ingredients (APIs) containing solid dosage forms. In this study, carbamazepine and indomethacin are used as models for poorly water-soluble APIs. First, we measured the T1 and T2 relaxation behavior of crystalline and amorphous APIs. From the results, we were able to confirm that the T1 relaxation time measured by TD-NMR is an effective parameter for distinguishing between crystalline and amorphous states in powdered APIs. We then examined physical mixtures of APIs with polyvinylpyrrolidone and their solid dispersion. The results indicated that TD-NMR allows the evaluation of not only the crystalline form of APIs but also the miscibility of APIs and polymers. In the final phase of the study, we conducted continuous monitoring of the crystalline state of APIs incorporated into physical mixtures during the thermal stress test. Conversion to crystalline forms of the APIs was successfully monitored based on the T1 relaxation behavior. Our findings led us to conclude that TD-NMR is useful as a new approach to evaluate the crystalline state of APIs.

Antimicrobial activity of pharmaceutical cocktails in sewage treatment plant effluent – An experimental and predictive approach to mixture risk assessment

Municipal wastewater contains multi-component mixtures of active pharmaceutical ingredients (APIs). This could shape microbial communities in sewage treatment plants (STPs) and the effluent-receiving ecosystems. In this paper we assess the risk of antimicrobial effects in STPs and the aquatic environment for a mixture of 18 APIs that was previously detected in the effluent of a European municipal STP. Effects on microbial consortia (collected from a separate STP) were determined using respirometry, enumeration of culturable microorganisms and community-level physiological profiling. The mixture toxicity against selected bacteria was assessed using assays with Pseudomonas putida and Vibrio fischeri. Additional data on the toxicity to environmental bacteria were compiled from literature in order to assess the individual and expected joint bacterial toxicity of the pharmaceuticals in the mixture. The reported effluent concentration of the mixture was 15.4 nmol/l and the lowest experimentally obtained effect concentrations (EC10) were 242 nmol/l for microbial consortia in STPs, 225 nmol/l for P. putida and 73 nmol/l for V. fischeri. The lowest published effect concentrations (EC50) of the individual antibiotics in the mixture range between 15 and 150 nmol/l, whereas 0.9–190 μmol/l was the range of bacterial EC50 values found for the non-antibiotic mixture components. Pharmaceutical cocktails could shape microbial communities at concentrations relevant to STPs and the effluent receiving aquatic environment. The risk of antimicrobial mixture effects was completely dominated by the presence of antibiotics, whereas other pharmaceutical classes contributed only negligibly to the mixture toxicity. The joint bacterial toxicity can be accurately predicted from the individual toxicity of the mixture components, provided that standardized data on representative bacterial strains becomes available for all relevant compounds. These findings argue for a more sophisticated bacterial toxicity assessment of environmentally relevant pharmaceuticals, especially for those with a mode of action that is known to specifically affect prokaryotic microorganisms.

Experimental cocrystal screening and solution based scale-up cocrystallization methods.

Cocrystals are crystalline single phase materials composed of two or more different molecular and/or ionic compounds generally in a stoichiometric ratio which are neither solvates nor simple salts. If one of the components is an active pharmaceutical ingredient (API), the term pharmaceutical cocrystal is often used. There is a growing interest among drug development scientists in exploring cocrystals, as means to address physicochemical, biopharmaceutical and mechanical properties and expand solid form diversity of the API. Conventionally, coformers are selected based on crystal engineering principles, and the equimolar mixtures of API and coformers are subjected to solution-based crystallization that are commonly employed in polymorph and salt screening. However, the availability of new knowledge on cocrystal phase behaviour in solid state and solutions has spurred the development and implementation of more rational experimental cocrystal screening as well as scale-up methods. This review aims to provide overview of commonly employed solid form screening techniques in drug development with an emphasis on cocrystal screening methodologies. The latest developments in understanding and the use of cocrystal phase diagrams in both screening and solution based scale-up methods are also presented. Final section is devoted to reviewing the state of the art research covering solution based scale-up cocrystallization process for different cocrystals besides more recent continuous crystallization methods.

Hazard screening of photo-transformation products from pharmaceuticals: Application to selective β1-blockers atenolol and metoprolol.

The identification of toxic components in cocktail mixtures of pollutants, their metabolites and transformation products (TPs) generated from environmental and treatment processes remains an arduous task. This study expanded in this area by applying a combination of chemical analytics, a battery of in vitro bioassays and an in silico "testing battery" to UV photolysis mixtures of active pharmaceutical ingredients. The objectives were to understand the toxic nature of the mixtures and to prioritize photo-TPs for risk analysis. The selective β1-blockers Atenolol (ATL) and Metoprolol (MTL) that are ubiquitous in the aquatic environment were used as an example. The photolysis mixtures were cytotoxic to Vibrio fischeri and mammalian cells but not mutagenic in the Ames test or genotoxic in the in vitro micronucleus and umu tests. Potentially hazardous TPs were proposed by relating the observed effects to the kinetics of TP occurrence and applying in silico toxicity predictions for individual photo-TPs. This model study was done to identify principal mechanisms rather than accurately simulating environmental transformation processes. Several photo-TPs were proposed to present a greater hazard than the selected β-blockers and therefore fate and toxicity assessments may be required to determine their environmental relevance.

Development of the composition and technology of the capsulated drug based on bee bread and honey powder. Report 2. The study of pharmacotechnological properties of the mixtures of active pharmaceutical ingredients with excipients of “Api-Immuno-Vit” caps

Development of the composition and technology of the capsulated drug based on bee bread and honey powder. Report 2. The study of pharmacotechnological properties of the mixtures of active pharmaceutical ingredients with excipients of “Api-Immuno-Vit” caps

Application of Melt Granulation Technology Using Twin-screw Extruder in Development of High-dose Modified-Release Tablet Formulation

Development of modified-release oral tablets of drug products usually requires release-modifying polymers at the level of above 50% of the total weight. This makes the development of high-dose products, especially with doses in the range of 750-1000 mg, difficult because the tablet size becomes unacceptably high. This report presents the development of high-dose modified-release formulation of an active pharmaceutical ingredient (API), imatinib mesylate, with a drug load of approximately 90%, by melt granulation using a twin-screw extruder. For an 800 mg dose, 956 mg of drug substance (salt) was needed and the final weight of tablet was approximately 1074 mg. By carefully selecting polymers based on their physicochemical properties, the release rate could be modified between desired times of 4 to >10 h for the total drug release. Mixtures of API and polymer were melt granulated at 185 °C, which is below the melting point of API (212 °C) but above the glass transition temperatures of polymers used. The confocal Raman microscopic imaging revealed that the API remained as unmelted, crystalline particles, and polymers were finely distributed on the surface and in between API particles. The formulations were found to be robust as no change in tableting and drug release properties was observed when manufacturing parameters were altered to challenge the process. The in vivo modified-release properties of formulations were demonstrated in human pharmacokinetic studies.

Analysis of Molecular Interactions in Solid Dosage Forms; Challenge to Molecular Pharmaceutics

The molecular states of active pharmaceutical ingredients (APIs) in pharmaceutical dosage forms strongly affect the properties and quality of a drug. Various important fundamental physicochemical studies were reviewed from the standpoint of molecular pharmaceutics. Mechanochemical effects were evaluated in mixtures of APIs and pharmaceutical additives. Amorphization, complex formation and nanoparticle formation are observed after grinding process depending on the combination of APIs and pharmaceutical additives. Sealed-heating method and mesoporous materials have been used to investigate drug molecular interactions in dosage forms. Molecular states have been investigated using powder X-ray diffraction, thermal analysis, IR, solid state fluorometry, and NMR.