Properties Of Active Pharmaceutical Ingredients Research Articles

Co-crystal Phase Diagram Determination by the Solution Addition Method

Multicomponent crystals such as co-crystals, salts, and solid solutions can be used to modify physical properties of active pharmaceutical ingredients. Phase diagrams of such multicomponent crystals are essential for crystallization process development, especially in the case where multiple solid phases may coexist. However, additional components and solid phases make phase diagrams more complex and their determination more time consuming. We propose to accelerate this process by identifying the eutectic points and constructing the rest of the phase diagram using thermodynamic models, informed by further measurements, if necessary. In this work, a novel solution addition method is proposed for determining the eutectic points in a co-crystal system. This method implements gradual compositional changes to traverse various regions of the phase diagram. Phase boundaries are determined by monitoring changes in the liquid phase (UV–vis) and solid phase (Raman), and eutectic points are obtained from intersection of phase boundaries. The results from solution addition are compared to those of an equilibration method, which combines gravimetry, XRPD, and NMR to identify the eutectic solution composition starting from a composition in the three-phase region of a co-crystal phase diagram. Both methods were able to locate all eutectic points, allowing construction of the ternary phase diagrams of benzoic acid and isonicotinamide in ethanol.

Controlled nucleation of crystallization process as an efficient tool to tune the properties of corticosteroid API

Crystallization as one of the final steps in the industrial production of active pharmaceutical ingredients (APIs) significantly influences their physicochemical and rheological properties. Different crystallization procedures including antisolvent crystallization, seeding crystallization, crystallization with templates and sonocrystallization were utilized for the production of corticosteroid APIs—fluticasone propionate. The final crystalline APIs obtained by individual crystallization procedures were characterized by a wide range of characterization techniques. We show that nucleation is a critical step that significantly affects APIs' properties. Controlled nucleation thus represents an easy method for managing these properties. Well-designed nucleation yields to crystalline products, which does not necessitate any post-processing including, e.g., micronization. These findings can be widely applied to the production of API with targeted properties.

Cocrystals of Praziquantel with Phenolic Acids: Discovery, Characterization, and Evaluation.

Solvent-assisted grinding (SAG) and solution slow evaporation (SSE) methods are generally used for the preparation of cocrystals. However, even by using the same solvent, active pharmaceutical ingredient (API), and cocrystal coformer (CCF), the cocrystals prepared using the two methods above are sometimes inconsistent. In the present study, in the cocrystal synthesis of praziquantel (PRA) with polyhydroxy phenolic acid, including protocatechuic acid (PA), gallic acid (GA), and ferulic acid (FA), five different cocrystals were prepared using SAG and SSE. Three of the cocrystals prepared using the SAG method have the structural characteristics of carboxylic acid dimer, and two cocrystals prepared using the SSE method formed cocrystal solvates with the structural characteristics of carboxylic acid monomer. For phenolic acids containing only one phenolic hydroxyl group (ferulic acid), when preparing cocrystals with PRA by using SAG and SSE, the same product was obtained. In addition, the weak molecular interactions that were observed in the cocrystal are explained at the molecular level by using theoretical calculation methods. Finally, the in vitro solubility of cocrystals without crystal solvents and in vivo bioavailability of PRA-FA were evaluated to further understand the influence on the physicochemical properties of API for the introduction of CCF.

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.

A new bioactive cocrystal of coumarin-3-carboxylic acid and thiourea: detailed structural features and biological activity studies.

Cocrystallization is a phenomenon widely used to enhance the biological and physicochemical properties of active pharmaceutical ingredients (APIs). The present study deals with the synthesis of a cocrystal of coumarin-3-carboxylic acid (2-oxochromene-3-carboxylic acid, C10H6O4), a synthetic analogue of the naturally occurring antioxidant coumarin, with thiourea (CH4N2S) using the neat grinding method. The purity and homogeneity of the coumarin-3-carboxylic acid-thiourea (1/1) cocrystal was confirmed by single-crystal X-ray diffraction, FT-IR analysis and thermal stability studies based on differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Detailed geometry analysis via density functional theory (DFT) demonstrated that the 1:1 cocrystal stoichiometry is sustained by N-H...O hydrogen bonding between the amine (-NH2) groups of thiourea and the carbonyl group of coumarin. The synthesized cocrystal exhibited potent antioxidant activity (IC50 = 127.9 ± 5.95 µM) in a DPPH radical scavenger assay in vitro in comparison with the standard N-acetyl-L-cysteine (IC50 = 111.6 ± 2.4 µM). The promising results of the present study highlight the significance of cocrystallization as a crystal engineering tool to improve the efficacy of pharmaceutical ingredients.

Molecular Structural, Hydrogen Bonding Interactions, and Chemical Reactivity Studies of Ezetimibe-L-Proline Cocrystal Using Spectroscopic and Quantum Chemical Approach.

Ezetimibe (EZT) being an anticholesterol drug is frequently used for the reduction of elevated blood cholesterol levels. With the purpose of improving the physicochemical properties of EZT, in the present study, cocrystals of ezetimibe with L-proline have been studied. Theoretical geometry optimization of EZT-L-proline cocrystal, energies, and structure–activity relationship was carried out at the DFT level of theory using B3LYP functional complemented by 6-311++G(d,p) basis set. To better understand the role of hydrogen bonding, two different models (EZT + L-proline and EZT + 2L-proline) of EZT-L-proline cocrystal were studied. Spectral techniques (FTIR and FT-Raman) combined with quantum chemical methodologies were successfully implemented for the detailed vibrational assignment of fundamental modes. It is a zwitterionic cocrystal hydrogen bonded with the OH group of EZT and the COO− group of L-proline. The existence and strength of hydrogen bonds were examined by a natural bond orbital analysis (NBO) supported by the quantum theory of atoms in molecule (QTAIM). Chemical reactivity was reflected by the HOMO–LUMO analysis. A smaller energy gap in the cocrystal in comparison to API shows that a cocrystal is softer and chemically more reactive. MEPS and Fukui functions revealed the reactive sites of cocrystals. The calculated binding energy of the cocrystal from counterpoise method was −11.44 kcal/mol (EZT + L-proline) and −26.19 kcal/mol (EZT + 2L-proline). The comparative study between EZT-L-proline and EZT suggest that cocrystals can be better used as an alternative to comprehend the effect of hydrogen bonding in biomolecules and enhance the pharmacological properties of active pharmaceutical ingredients (APIs).

Characterization of the Salt and Free Base of Active Pharmaceutical Ingredients Based on NMR Relaxometry Measured by Time Domain NMR.

NMR relaxometry measurement by time domain NMR (TD-NMR) is a promising technique for characterizing the properties of active pharmaceutical ingredients (APIs). This study is dedicated to identifying the salt and free base of APIs by NMR relaxometry measured by the TD-NMR technique. Procaine (PC) and tetracaine (TC) were selected as model APIs to be tested. By using conventional methods including powder X-ray diffraction and differential scanning calorimetry, this study first confirmed that the salt and free base of the tested APIs differ from each other in their crystalline form. Subsequently, measurements of T1 and T2 relaxation were performed on the tested APIs using TD-NMR. The results demonstrated that these NMR relaxometry measurements have sufficient capacity to distinguish the difference between the free base and salt of the tested APIs. Furthermore, quantification of the composition of the binary powder blends consisting of salt and free bases was conducted by analyzing the acquired T1 and T2 relaxation curves. The analysis of the T1 relaxation curves provided a partly acceptable estimation: a good estimation of the composition was observed from PC powders, whereas for TC powders the estimation accuracy changed with the free base content in the binary blends. For the analysis on T2 relaxation curves, a precise estimation of the composition was observed from all the samples. From these findings, the NMR relaxometry measurement by TD-NMR, in particular the T2 relaxation measurement, is effective for evaluating the properties of APIs having different crystalline forms.

Improving hygroscopic stability of palmatine by replacing Clˉ and preparing single crystal of palmatine-salicylic acid

In order to improve the hygroscopic stability of palmatine (PMT), an unreported single crystal of palmatine-salicylic acid (PMT-SA, [C21H22NO4]C7H5O3) was designed and synthesized by replacing Clˉ of PMTCl, and the hygroscopic stability of PMT was remarkably improved. The crystal structures and intermolecular interactions were characterized by single crystal X-ray diffraction, elemental analysis, NMR (1H and 13C), FT-IR, PXRD, TGA-DSC and Hirshfeld surface analysis, and its properties were studied. Single crystal X-ray diffraction analysis revealed that asymmetric unit of PMT-SA contains one PMT and one SA, and adjacent asymmetric unit are connected via hydrogen bond C6-H6A…O6 to form an annular synthon R44(22). Adjacent synthons form 1D chain by intermolecular hydrogen bond C25-H25…O5 and π…π packing, as if PMT+ are sandwiched between SAˉ chains. Furthermore, 1D chains are interwoven through C27-H27…O5 of SAˉ chains on the both sides to fabricate 2D layers, then 2D layers overlaps into a fascinating 3D framework. Comprehensive structural analysis and Hirshfeld surface analysis reveal that the weak interaction force of hydrogen bonds formed between H atom of aromatic ring in PMT and carboxylic acid group of SA can promote stable crystal structure. Hygroscopic stability and DVS experiments show that hygroscopic stability of PMT-SA is tremendously enhanced, which might attribute to the replacement of Clˉ by SAˉ and the preparation of PMT-SA with a stable crystal structure. This successful work implies that a new approach to design protoberberines pharmaceutical salt with good hygroscopic stability by replacing anions, and provides inspiration for improving physicochemical properties of active pharmaceutical ingredients. Further to this, antibacterial activities of PMT-SA resist Staphylococcus aureus, Staphylococcus albus, and Escherichia coli are higher than PMTCl in vitro at gradient concentrations.

Characterizing the Physicochemical Properties of Two Weakly Basic Drugs and the Precipitates Obtained from Biorelevant Media.

Generally, some weakly basic insoluble drugs will undergo precipitate and redissolution after emptying from the stomach to the small intestinal, resulting in the limited ability to predict the absorption characteristics of compounds in advance. Absorption is determined by the solubility and permeability of compounds, which are related to physicochemical properties, while knowledge about the absorption of redissolved precipitate is poorly documented. Considering that biorelevant media have been widely used to simulate gastrointestinal fluids, sufficient precipitates can be obtained in biorelevant media in vitro. Herein, the purpose of this manuscript is to evaluate the physicochemical properties of precipitates obtained from biorelevant media and active pharmaceutical ingredients (API), and then to explore the potential absorption difference between API and precipitates. Precipitates can be formed by the interaction between compounds and intestinal fluid contents, leading to changes in the crystal structure, melting point, and melting process. However, the newly formed crystals have some advantageous properties compared with the API, such as the improved dissolved rate and the increased intrinsic dissolution rate. Additionally, the permeability of some precipitates obtained from biorelevant media was different from API. Meanwhile, the permeability of rivaroxaban and Drug-A was decreased by 1.92-fold and 3.53-fold, respectively, when the experiments were performed in a biorelevant medium instead of a traditional medium. Therefore, the absorption of precipitate may differ from that of API, and the permeability assay in traditional medium may be overestimated. Based on the research results, it is crucial to understand the physicochemical properties of precipitates and API, which can be used as the departure point to improve the prediction performance of absorption.

Topologically directed confocal Raman imaging (TD-CRI): Advanced Raman imaging towards compositional and micromeritic profiling of a commercial tablet components

Particle size distribution (PSD), spatial location and particle cluster size of ingredients, polymorphism, compositional distribution of a pharmaceutical product are few of the most important attributes in establishing the drug release-controlling microstructural and solid state properties that would be used to (re)design or reproduce similar products. There are numerous solid-state techniques available for PSD analysis. Laser diffraction (LD) is mostly used to study PSD of raw materials. However, a constraint of LD is the interference between the active pharmaceutical ingredients (API) and excipients, where it is very challenging to measure API size in a tablet. X-ray powder diffraction (XRPD) is widely employed in establishing the polymorphism of API and excipients. This research examined a commercial osmotic tablet in terms of extracting solid state properties of API and functional excipient by Raman Imaging. Establishing repeatability, reproducibility, and sample representativeness when the samples are non-uniform and inhomogeneous necessitates multiple measurements. In such scenarios, when employing imaging-based techniques, it can be time-consuming and tedious. Advanced statistical methodologies are used to overcome these disadvantages and expedite the characterization process. Overall, this study demonstrates that Raman imaging can be employed as a non-invasive and effective offline method for assessing the solid-state characteristics of API and functional excipients in complex dosage forms like osmotic tablets.

Multicomponent crystal compromising dasatinib and selected co-crystals formers: a patent evaluation of EP2861589B1.

Cocrystallization has gained significant prominence in pharmaceutical product development because of the enhancement of physical, chemical and pharmacological properties of active pharmaceutical ingredients, such as stability, solubility, dissolution rate, taste, hygroscopicity, mechanical property, bioavailability, permeability and therapeutic activity. Traditionally, co-crystals can be prepared by a grinding, solvent evaporation and slurry method. However, sophisticated methods such as spa drying, hot-melt extrusion, supercritical fluid and laser irradiation are also reported to be used for producing co-crystals. The selected patent describes the development of multicomponent crystals of dasatinib, with an aim to enhance the aqueous solubility of a selected drug. However issues surrounding the toxicity, stability, large scale manufacture, in vivo performance in human beings and regulations require adequate addressal prior to exploring the commercial viability of pharmaceutical co-crystals.

Green Synthesis, Structural Characterization and Biological Activity of Diclofenac-Urea Co-Crystal

Co-crystals have become an area of research interest for pharmaceutical drug improvements due to their characteristic nature in modifying the physico-chemical properties of active pharmaceutical ingredients (APIs) with the aid of a co-former. Co-crystals improve the solubility, dissolution rate, melting point, and stability of the API without changing the chemical identity nor diminishing the biological activity or the therapeutic effect of the API. This work reports the green synthetic approach to synthesize Diclofenac-Urea (DUREA) co-crystal using a benign solvent and stirring at room temperature, all in an environmentally friendly manner. The synthesis of DUREA was accomplished by reaction of a 1:1 molar ratio of diclofenac potassium and urea and the product gave a white crystalline compound with an excellent yield (91%). The product (DUREA) was structurally characterized using melting point, UV/VIS, and FT-IR spectrophotometry. The antimicrobial activity of the co-crystal was tested against Salmonella typi and Proteus mirablis.

Superior Dissolution Behavior and Bioavailability of Pharmaceutical Cocrystals and Recent Regulatory Issues.

Cocrystallization has been used extensively to optimize the physicochemical properties of active pharmaceutical ingredients (APIs), such as stability, dissolution, and bioavailability. This review summarizes the history and development of cocrystals, the differences between pharmaceutical cocrystals and salts, and the mechanism underlying the improvement of dissolution through cocrystallization. The correlation of in vitro dissolution and in vivo absorption data (IVIVC) of cocrystals has been discussed as well. Subsequently, guidelines for regulatory classification of cocrystals by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) are introduced. Finally, d-α-tocopherol is used as an example to demonstrate the potential of cocrystals in patent generation.

Thermodynamic properties of active pharmaceutical ingredients that are of interest in COVID-19

The pure component properties are estimated for active pharmaceutical ingredients that are related or proposed for the treatment of severe acute respiratory syndrome-CoronaVirus-2. These include Baricitinib, Camostat, Chloroquine, Dexamethasone, Hydroxychloroquine, Fingolimod, Favipiravir, Thalidomide, and Umifenovir. The estimations are based on group contribution+ (GC) models that contain combined group contribution and atom connectivity index with uncertainties in the estimated property values. The thermodynamic properties that are reported include boiling point, critical temperature, critical pressure, critical volume, melting point, standard Gibb's energy of formation, standard enthalpy of formation, enthalpy of fusion, enthalpy of vaporization at 298 K, enthalpy of vaporization at boiling point, entropy of vaporization at boiling point, flash point, Hildebrand solubility parameter, octanol/water partition coefficient, acentric factor, and liquid molar volume at 298 K. The reported properties are not available in the literature and thereby is an incremental development for reliable process engineering.

Improving the Physicochemical and Biopharmaceutical Properties of Active Pharmaceutical Ingredients Derived from Traditional Chinese Medicine through Cocrystal Engineering.

Active pharmaceutical ingredients (APIs) extracted and isolated from traditional Chinese medicines (TCMs) are of interest for drug development due to their wide range of biological activities. However, the overwhelming majority of APIs in TCMs (T-APIs), including flavonoids, terpenoids, alkaloids and phenolic acids, are limited by their poor physicochemical and biopharmaceutical properties, such as solubility, dissolution performance, stability and tabletability for drug development. Cocrystallization of these T-APIs with coformers offers unique advantages to modulate physicochemical properties of these drugs without compromising the therapeutic benefits by non-covalent interactions. This review provides a comprehensive overview of current challenges, applications, and future directions of T-API cocrystals, including cocrystal designs, preparation methods, modifications and corresponding mechanisms of physicochemical and biopharmaceutical properties. Moreover, a variety of studies are presented to elucidate the relationship between the crystal structures of cocrystals and their resulting properties, along with the underlying mechanism for such changes. It is believed that a comprehensive understanding of cocrystal engineering could contribute to the development of more bioactive natural compounds into new drugs.

Towards Continuous Primary Manufacturing Processes—Particle Design through Combined Crystallization and Particle Isolation

Integrated continuous manufacturing processes of active pharmaceutical ingredients (API) provide key benefits concerning product quality control, scale-up capability, and a reduced time-to-market. Thereby, the crystallization step, which is used in approximately 90% of API productions, mainly defines the final API properties. This study focuses on the design and operation of an integrated small-scale process combining a continuous slug flow crystallizer (SFC) with continuous particle isolation using the modular continuous vacuum screw filter (CVSF). By selective adjustment of supersaturation and undersaturation, the otherwise usual blocking could be successfully avoided in both apparatuses. It was shown that, during crystallization in an SFC, a significant crystal growth of particles (Δd50,3≈ 220 µm) is achieved, and that, during product isolation in the CVSF, the overall particle size distribution (PSD) is maintained. The residual moistures for the integrated process ranged around 2% during all experiments performed, ensuring free-flowing particles at the CVSF outlet. In summary, the integrated setup offers unique features, such as its enhanced product quality control and fast start-up behavior, providing a promising concept for integrated continuous primary manufacturing processes of APIs.

Solubility Enhancement of Antidiabetic Drugs Using a Co-Crystallization Approach.

The co‐crystallization approach has been used to enhance specific desirable properties of active pharmaceutical ingredients (APIs) such as solubility, dissolution rate, and stability. Solubility is a fundamental property that affects the bioavailability and dosage of the API. The co‐crystal approach is one of the emerging methods with the potential for improving the solubility of these drugs. This paper reviews the latest progress on improving the solubility of some antidiabetic drug molecules using the co‐crystal approach.

Characterization of Tableting Speed-Dependent Deformation Properties of Active Pharmaceutical Ingredients in Powder Mixtures Using Out-of-Die Method.

A quantitative evaluation method for determining the effect of tableting speed on the compression properties of pharmaceutical powders was investigated in this study. Cilostazol and ibuprofen were used as active pharmaceutical ingredients (APIs) and mixed with lactose monohydrate and microcrystalline cellulose. Viscoelasticity was examined to evaluate the raw material, and stress relaxation tests were conducted to determine the apparent viscosity and elasticity coefficients of the placebo and two APIs. Tablets were prepared using a compaction simulator and a rotary tablet press at the tableting speeds ranging from laboratory to commercial. The in-die or out-of-die strain rate sensitivity (SRS) indices were determined as a measure of the compressibility and compactibility. The results showed that the sensitivity of the out-of-die SRS was higher than that of the in-die SRS. The out-of-die SRS of ibuprofen 20% powder, which showed high elasticity and low viscosity, was 13.3-47.9%, whereas that of the placebo and cilostazol 20% (w/w) powder was <7.5%. A peripheral speed difference of more than 300 mm/s during the out-of-die SRS was sensitive enough to detect the capping tendency. Cilostazol, which has lower elasticity and higher viscosity than ibuprofen, was tested using powder mixtures with the API concentrations of 5-40%; the compressibility SRS was <5% for all API concentrations. In contrast, the compressibility SRS of ibuprofen increased from 4.8 to 81% depending on the API concentration. Using the compressibility SRS as an index, it was possible to extract the tableting speed-dependent compressibility characteristics of API from the powder mixtures containing API.

Drastic Modulation of Molecular Packing and Intrinsic Dissolution Rates by Meniscus-Guided Coating of Extremely Confined Pharmaceutical Thin Films.

Nanosizing has emerged as one of the most effective formulation strategies for enhancement of dissolution properties of active pharmaceutical ingredients (APIs). In addition to enhancing the specific area of the dissolving solids, nanosizing can also capture and stabilize the metastable form of the API, which can further enhance the solubility by drastic modulation of surface energies. Herein, we employ meniscus-guided coating to fabricate nanothin films of three APIs that show anticancer properties and are poorly soluble:10-HCPT, SN-38, and amonafide. By modulating the coating speed, we systematically deposited the APIs in films ranging from ∼200 nm thickness to extreme confinement of ∼10 nm (<10 molecular layers). In all three APIs, we observe a general order-to-disorder transition with semicrystalline (10-HCPT and amonafide) or amorphous (SN-38) form of API solids trapped in thin films when the thickness decreases below a critical value of ∼25-30 nm. The existence of a critical thickness highlights the importance of nanoconfinement in tuning molecular packing. In the case of 10-HCPT, we demonstrate that the disordered form of the API occurs largely due to lack of incorporation of water molecules in thinner films below the critical thickness, thereby disrupting the three-dimensional hydrogen-bonded network held by water molecules. We further developed a dissolution model that predicts variation of the intrinsic dissolution rate (IDR) with API film thickness, which also closely matched with experimental results. We achieved drastic improvement in the IDR of ∼240% in 10-HCPT by decreasing film thickness alone. Further leveraging the order-to-disorder transition led to 2570% modulation of the IDR for amonafide. Our work demonstrates, for the first time, opportunities to largely modulate API dissolution by precisely controlling the dimensionality of thin films.

Furosemide/Non-Steroidal Anti-Inflammatory Drug–Drug Pharmaceutical Solids: Novel Opportunities in Drug Formulation

The design of drug–drug multicomponent pharmaceutical solids is one the latest drug development approaches in the pharmaceutical industry. Its purpose is to modulate the physicochemical properties of active pharmaceutical ingredients (APIs), most of them already existing in the market, achieving improved bioavailability properties, especially on oral administration drugs. In this work, our efforts are focused on the mechanochemical synthesis and thorough solid-state characterization of two drug–drug cocrystals involving furosemide and two different non-steroidal anti-inflammatory drugs (NSAIDs) commonly prescribed together: ethenzamide and piroxicam. Besides powder and single crystal X-ray diffraction, infrared spectroscopy and thermal analysis, stability, and solubility tests were performed on the new solid materials. The aim of this work was evaluating the physicochemical properties of such APIs in the new formulation, which revealed a solubility improvement regarding the NSAIDs but not in furosemide. Further studies need to be carried out to evaluate the drug–drug interaction in the novel multicomponent solids, looking for potential novel therapeutic alternatives.