Preparation and Characterization of a Rifampicin Coamorphous Material with Tromethamine Coformer: An Experimental-Theoretical Study.

Rifampicin (RIF) is an antibiotic used to treat tuberculosis and leprosy. Even though RIF is a market-available drug, it has a low aqueous solubility, hindering its bioavailability. Among the strategies for bioavailability improvement of poorly soluble drugs, coamorphous systems have been revealed as an alternative in the increase of the aqueous solubility of drug systems and at the same time also increasing the amorphous state stability and dissolution rate when compared with the neat drug. In this work, a new coamorphous form from RIF and tromethamine (TRIS) was synthesized by slow evaporation. Structural, electronic, and thermodynamic properties and solvation effects, as well as drug-coformer intermolecular interactions, were studied through density functional theory (DFT) calculations. Powder X-ray diffraction (PXRD) data allowed us to verify the formation of a new coamorphous. In addition, the DFT study indicates a possible intermolecular interaction by hydrogen bonds between the available amino and carbonyl groups of RIF and the hydroxyl and amino groups of TRIS. The theoretical spectra obtained are in good agreement with the experimental data, suggesting the main interactions occurring in the formation of the coamorphous system. PXRD was used to study the physical stability of the coamorphous system under accelerated ICH conditions (40 °C and 75% RH), indicating that the material remained in an amorphous state up to 180 days. The thermogravimetry result of this material showed a good thermal stability up to 153 °C, and differential scanning calorimetry showed that the glass temperature (Tg) was at 70.0 °C. Solubility studies demonstrated an increase in the solubility of RIF by 5.5-fold when compared with its crystalline counterpart. Therefore, this new material presents critical parameters that can be considered in the development of new coamorphous formulations.

Computational-Based Polyphenol Therapy for Nonsmall Cell Lung Cancer: Naringin Coamorphous Systems for Solubility and Bioavailability Enhancement.

In this research, we utilized molecular simulations to create co-amorphous materials (CAMs) of ceritinib (CRT) with the objective of improving its solubility and bioavailability. We identified naringin (NRG) as a suitable co-former for CRT CAMs based on binding energy and intermolecular interactions through computational modeling. We used the solvent evaporation method to produce CAMs of CRT and NRG, expecting to enhance both solubility and bioavailability simultaneously. The solid-state characterization using techniques like differential scanning calorimeter, X-ray powder diffraction, and Fourier-transform infrared spectroscopy affirmed the formation of a single amorphous phase and the presence of intermolecular interactions between CRT and NRG in the CAMs. These materials remained physically stable for up to six months under dry conditions at 40 °C. Moreover, the CAMs demonstrated significant improvements in the solubility and dissolution of CRT (specifically in the ratio CRT:NRG 1:2). This, in turn, led to an increase in cytotoxicity, apoptotic cells, and G0/G1 phase inhibition in A549 cells compared to CRT alone. Furthermore, CRT permeability is also improved twofold, as estimated by the everted gut sac method. The enhanced solubility of CAMs also positively affected the pharmacokinetic parameters. When compared to the physical mixture, the CAMs of CRT:NRG 2:1 exhibited a 2.1-fold increase in CRT exposure (AUC0-t) and a 2.4-fold increase in plasma concentration (Cmax).

Effects of Polymers on Cocrystal Growth in a Drug-Drug Coamorphous System: Relations between Glass-to-Crystal Growth and Surface-Enhanced Crystal Growth.

Coamorphous and cocrystal drug delivery systems provide attractive crystal engineering strategies for improving the solubilities, dissolution rates, and oral bioavailabilities of poorly water-soluble drugs. Polymeric additives have often been used to inhibit the unwanted crystallization of amorphous drugs. However, the transformation of a coamorphous phase to a cocrystal phase in the presence of polymers has not been fully elucidated. Herein, we investigated the effects of low concentrations of the polymeric excipients poly(ethylene oxide) (PEO) and poly(vinylpyrrolidone) (PVP) on the growth of carbamazepine-celecoxib (CBZ-CEL) cocrystals from the corresponding coamorphous phase. PEO accelerated the growth rate of the cocrystals by increasing the molecular mobility of the coamorphous system, while PVP had the opposite effect. The coamorphous CBZ-CEL system exhibited two anomalously fast crystal growth modes: glass-to-crystal (GC) growth in the bulk and accelerated crystal growth at the free surface. These two fast growth modes both disappeared after doping with PEO (1-3% w/w) but were retained in the presence of PVP, indicating a potential correlation between the two fast crystal growth modes. We propose that the different effects of PEO and PVP on the crystal growth modes arose from weaker effects of the polymers on cocrystallization at the surface than in the bulk. This work provides a deep understanding of the mechanisms by which polymers influence the cocrystallization kinetics of a multicomponent amorphous phase and highlights the importance of polymer selection in stabilizing coamorphous systems or preparing cocrystals via solid-based methods.

New Perspectives for Antihypertensive Sartans as Components of Co-crystals and Co-amorphous Solids with Improved Properties and Multipurpose Activity.

Sartans (angiotensin II receptor blockers, ARBs), drugs used in the treatment of hypertension, play a principal role in addressing the global health challenge of hypertension. In the past three years, their potential use has expanded to include the possibility of their application in the treatment of COVID-19 and neurodegenerative diseases (80 clinical studies worldwide). However, their therapeutic efficacy is limited by their poor solubility and bioavailability, prompting the need for innovative approaches to improve their pharmaceutical properties. This review discusses methods of co-crystallization and co-amorphization of sartans with nonpolymeric, low molecular, and stabilizing co-formers, as a promising strategy to synthesize new multipurpose drugs with enhanced pharmaceutical properties. The solid-state forms have demonstrated the potential to address the poor solubility limitations of conventional sartan formulations and offer new opportunities to develop dual-active drugs with broader therapeutic applications. The review includes an in-depth analysis of the co-crystal and co-amorphous forms of sartans, including their properties, possible applications, and the impact of synthetic methods on their pharmacokinetic properties. By shedding light on the solid forms of sartans, this article provides valuable insights into their potential as improved drug formulations. Moreover, this review may serve as a valuable resource for designing similar solid forms of sartans and other drugs, fostering further advances in pharmaceutical research and drug development.

Improved Dissolution Properties of Co-amorphous Probucol with Atorvastatin Calcium Trihydrate Prepared by Spray-Drying.

A co-amorphous model drug was prepared by the spray-drying (SD) of probucol (PC) and atorvastatin calcium trihydrate salt (ATO) as low water solubility and co-former components, respectively. The physicochemical properties of the prepared samples were characterized by powder X-ray diffraction (PXRD) analysis, thermal analysis, Fourier transform infrared spectroscopy (FTIR), and dissolution tests. Stability tests were also conducted under a stress environment of 40 °C and 75% relative humidity. The results of PXRD measurements and thermal analysis suggested that PC and ATO form a co-amorphous system by SD. Thermal analysis also indicated an endothermic peak that followed an exotherm in amorphous PC and a physical mixture (PM) of amorphous PC and ATO; however, no endothermic peak was detected in the co-amorphous system. The dissolution profiles for PC in the co-amorphous sample composed of PC and ATO were improved compared to those for raw PC crystals or the PM. Stability tests indicated that the co-amorphous material formed by PC and ATO can be stored for 35 d without crystallization, whereas amorphous PC became crystallized within a day. Therefore, co-amorphization of PC and ATO prepared by SD is considered to be a useful method to improve the solubility of PC in water.

Effect of food on oral pharmacokinetics of edaravone coamorphous dispersion containing bile salts as coformers - Part II.

OBJECTIVES: Edaravone (EDR) is an effective neuroprotective agent in various neurological diseases; however, its use is restricted due to poor oral absorption. Bile salts are known for improving solubility and inhibiting drug crystallization in supersaturated conditions of the gastrointestinal tract (GIT). In our previous work, we prepared coamorphous dispersion (COAM) of EDR with sodium taurocholate (NaTC) using spray drying. The optimized EDR COAM exhibited superior in vitro performance compared to plain EDR. EDR is well absorbed in fasted-over-fed conditions. METHODS: The present work, we conducted a pharmacokinetic study for EDR and EDR COAM in fasted and fed conditions to check effect of food on its oral absorption. The LC-MS/MS-based method was developed and validated to determine the amount of EDR in plasma. RESULTS: The results suggested that EDR COAM did not show a significant difference in Cmax (P=0.3544) and AUC (P=0.1696) of fasted and fed states. On the other hand, plain EDR showed 2-fold and 3-fold reduced Cmax (P<0.0001) and AUC (P=0.0094) in the fed condition, respectively. The Cmax and AUC of EDR COAM were improved in fasted (AUC: 2.56-fold) and fed states (AUC: 5.74-fold) than plain EDR, suggesting better oral absorption of COAM than crystalline EDR without having the effect of food. CONCLUSIONS: The unique structural attributes of NaTC had the potential to inhibit the recrystallization of EDR in GIT, while concurrently reducing the impact of food on the oral absorption of EDR.

Influence of Co-amorphization on the Physical Stability and Dissolution Performance of an Anthelmintic Drug Flubendazole.

In this work, the co-amorphization approach was applied to flubendazole (FluBZ), resulting in the formation of two novel solid forms of FluBZ with l-phenylalanine (Phe) and l-tryptophan (Trp). A variety of physicochemical techniques have been used to describe new systems, including powder X-ray diffraction, thermal methods, infrared spectroscopy, and scanning electron microscopy. Co-amorphization has been shown to suppress crystallization tendency and considerably increase the shelf-life storage of amorphous flubendazole solid across a wide range of relative humidities. The dissolution behavior of the amorphous forms in biorelevant media at pH = 1.6, pH = 6.5, and 37 °C has been studied in terms of Cmax (maximum FluBZ concentration), Tmax (time to attain peak drug concentration), and AUC (concentration area under the curve during dissolution). At pH = 6.5, a continuous supersaturation and the highest AUC value of all examined systems were observed for the FluBZ-Phe (1:1) system. The phase solubility diagrams revealed that the reason for the better dissolution performance of FluBZ-Phe (1:1) at pH = 6.5 is a complexation between the components in a solution. This work highlights the applicability of co-amorphous systems in improving the physical stability and dissolution performance of drug compounds with poor biopharmaceutical characteristics.

Improvement in Inhalation Properties of Theophylline and Levofloxacin by Co-Amorphization and Enhancement in Its Stability by Addition of Amino Acid as a Third Component.

Co-amorphous systems are amorphous formulations stabilized by the miscible dispersion of small molecules. This study aimed to design a stable co-amorphous system for the co-delivery of two drugs to the lungs as an inhaled formulation. Theophylline (THE) and levofloxacin (LEV) were used as model drugs for treating lung infection with inflammation. Leucine (LEU) or tryptophan (TRP) was employed as the third component to improve the inhalation properties. The co-amorphous system containing THE and LEV in an equal molar ratio was successfully prepared via spray drying where reduction of the particle size and change to the spherical morphology were observed. The addition of LEU or TRP at a one-tenth molar ratio to THE-LEV did not affect the formation of the co-amorphous system, but only TRP acted as an antiplasticizer. The Fourier transform infrared spectroscopy spectra revealed intermolecular interactions between THE and LEV in the co-amorphous system that were retained after the addition of LEU or TRP. The co-amorphous THE-LEV system exhibited better in vitro aerodynamic performance than a physical mixture of these compounds and permitted the simultaneous delivery of both drugs in various stages. The co-amorphous THE-LEV system crystallized at 40 °C, and this crystallization was not prevented by LEU. However, THE-LEV-TRP maintained its amorphous state for 1 month. Thus, TRP can act as a third component to improve the physical stability of the co-amorphous THE-LEV system, while maintaining the enhanced aerodynamic properties.

Designing a Novel Coamorphous Salt Formulation of Telmisartan with Amlodipine to Enhance Permeability and Oral Absorption.

Coamorphous formulation is a useful approach for enhancing the solubility of poorly water-soluble drugs via intermolecular interactions. In this study, a hydrogen-bonding-based coamorphous system was developed to improve drug solubility, but it barely changed the apparent permeability (Papp) of the drug. This study aimed to design a novel coamorphous salt using ionic interactions to improve drug permeability and absorption. Telmisartan (TMS), with an acidic group, was used to form a coamorphous salt with basic amlodipine (AML). Evaluation of the physicochemical properties confirmed the formation of a coamorphous salt via ionic interactions between the amine group of AML and the carboxyl group of TMS at a molar ratio of 1:1. The coamorphous salt of TMS/AML enhanced the partitioning of both drugs into octanol, indicating increased lipophilicity owing to the interaction between TMS and AML. The coamorphous salt dramatically enhanced TMS solubility (99.8 times that of untreated TMS) and decreased AML solubility owing to the interaction between TMS and AML. Although the coamorphous salt showed a decreased Papp in the permeation study in the presence of a thicker unstirred water layer (UWL) without stirring, Papp increased in the presence of a thinner UWL with stirring. The oral absorption of TMS from the coamorphous salt increased by up to 4.1 times compared to that of untreated TMS, whereas that of AML remained unchanged. Although the coamorphous salt with increased lipophilicity has a disadvantage in terms of diffusion through the UWL, the UWL is thin in human/animal bodies owing to the peristaltic action of the digestive tract. Dissociation of the coamorphous salt on the membrane surface could contribute to the partitioning of the neutral form of drugs to the membrane cells compared with untreated drugs. As a result, coamorphous salt formation has the advantage of improving the membrane permeation and oral absorption of TMS, owing to the enhanced solubility and supply of membrane-permeable free TMS on the surface of the membrane.

Switch between Cocrystal and Coamorphous Forms Depending on Thermal Modulation of Hot-Melt Extrusion.

Cocrystal (CC) and coamorphous (CM) techniques have become green technologies to improve the solubility and bioavailability of water-soluble drugs. In this study, hot-melt extrusion (HME) was employed to produce CC and CM formulations of indomethacin (IMC) and nicotinamide (NIC) due to its advantages like solvent-free and large-scale manufacturing. Interestingly, for the first time, IMC-NIC CC and CM were selectively prepared depending on the barrel temperatures of HME at a constant screw speed of 20 rpm and a feed rate of 1.0 g/min. IMC-NIC CC was obtained at 105-120 °C, IMC-NIC CM was produced at 125-150 °C, and the mixture of CC and CM was obtained between 120 and 125 °C (like a door switch of CC and CM). SS NMR combined with RDF and Ebind calculations revealed the formation mechanisms of CC and CM, where strong interactions between heteromeric molecules formed at lower temperatures favored periodic molecular organization of CC, whereas discrete and weak interactions formed at higher temperatures promoted disordered molecular arrangement of CM. Additionally, IMC-NIC CC and CM showed enhanced dissolution and stability over crystalline/amorphous IMC. This study provides an easy-to-operate and environmentally friendly strategy for the flexible regulation of CC and CM formulations with different properties through modulation of the barrel temperature of HME.

Coformer-Dependent Physical Stability in a Series of Naringenin-Based Coamorphous Materials with Caffeine, Theophylline, and Theobromine.

PURPOSE: To investigate the production and physical stability of coamorphous materials (CAM) of naringenin (NAR) and coformers-caffeine, theophylline or theobromine (CAF/THY/THE, respectively). We independently assessed the impact of moisture and temperature on the physical stability of CAMs, and transformation products after destabilization were examined. METHODS: Neat grinding, liquid assisted grinding and water slurry were selected to prepare multi-component materials with NAR and CAF, THY or THE. The physical stability of CAMs was investigated at 65°C/<10%RH, 21°C/85% RH and 21°C/<10% RH. Differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) were employed to monitor for recrystallization during the stability studies. Glass forming ability of amorphous NAR was assessed to understand CAM formation and physical stability. RESULTS: NAR:THY and NAR:THE CAMs showed physical stability for approximately nine months, under 21°C/<10% RH while NAR:CAF CAMs destabilized in 2.5 weeks. All CAMs recrystallized within a week at 65°C/<10%RH, and the physical stability at 21°C/85% RH was in the order of - NAR:THY > NAR:THE > NAR:CAF. NAR:THY produced 1:1 cocrystal under all storage conditions, while NAR:CAF destabilized to a 1:1 cocrystal at high RH but a physical mixture at high temperature. NAR:THE was found to recrystallize as a physical mixture in all conditions. NAR was found to be strong glass, with moderate kinetic fragility and good glass forming ability. CONCLUSION: Five naringenin-based multi-component solids were generated in this study: 3 new CAMs, 1 new cocrystal, and 1 previously reported cocrystal. Destabilization of CAMs was found to be exposure specific and coformer dependent.

Sinapic Acid Co-Amorphous Systems with Amino Acids for Improved Solubility and Antioxidant Activity.

The objective of this study was to obtain co-amorphous systems of poorly soluble sinapic acid using amino acids as co-formers. In order to assess the probability of the interaction of amino acids, namely, arginine, histidine, lysine, tryptophan, and proline, selected as co-formers in the amorphization of sinapic acid, in silico studies were carried out. Sinapic acid systems with amino acids in a molar ratio of 1:1 and 1:2 were obtained using ball milling, solvent evaporation, and freeze drying techniques. X-ray powder diffraction results confirmed the loss of crystallinity of sinapic acid and lysine, regardless of the amorphization technique used, while remaining co-formers produced mixed results. Fourier-transform infrared spectroscopy analyses revealed that the co-amorphous sinapic acid systems were stabilized through the creation of intermolecular interactions, particularly hydrogen bonds, and the potential formation of salt. Lysine was selected as the most appropriate co-former to obtain co-amorphous systems of sinapic acid, which inhibited the recrystallization of sinapic acid for a period of six weeks in 30 °C and 50 °C. Obtained co-amorphous systems demonstrated an enhancement in dissolution rate over pure sinapic acid. A solubility study revealed a 12.9-fold improvement in sinapic acid solubility after introducing it into the co-amorphous systems. Moreover, a 2.2-fold and 1.3-fold improvement in antioxidant activity of sinapic acid was observed with respect to the ability to neutralize the 2,2-diphenyl-1-picrylhydrazyl radical and to reduce copper ions, respectively.

Coamorphous Systems of Valsartan: Thermal Analysis Contribution to Evaluate Intermolecular Interactions Effects on the Structural Relaxation.

Coamorphous formation in binary systems of valsartan (Val) with 4,4'-bipyridine (Bipy) and trimethoprim (Tri) was investigated for mixtures with a mole fraction of 0.16~0.86 of valsartan and evaluated in terms of the glass transition temperature. The glass transition of the systems had a behavior outside the values predicted by the Gordon-Taylor equation, showing that Val-Bipy (hydrogen bonding between the components) had a lower deviation and Val-Tri (ionic bonding between the components) had a higher deviation. Mixtures of compositions 2:1 Val-Bipy and 1:1 Val-Tri were selected for further investigation and verified to be stable, as no crystallization was observed during subsequent heating and cooling programs. For these systems, the effective activation energy during glass transition was evaluated. Compared to pure valsartan, the system with the lower glass transition temperature (Val-Bipy) presented the highest effective activation energy, and the system with the higher glass transition temperature (Val-Tri) presented a lower effective activation energy. The results presented a good correlation between the data obtained from two different techniques to determine the fragility and effective activation energy: non-isothermal kinetic analysis by DSC and TSDC.

Solid-Liquid Equilibrium in Co-Amorphous Systems: Experiment and Prediction.

In this work, the solid-liquid equilibrium (SLE) of four binary systems combining two active pharmaceutical ingredients (APIs) capable of forming co-amorphous systems (CAMs) was investigated. The binary systems studied were naproxen-indomethacin, naproxen-ibuprofen, naproxen-probucol, and indomethacin-paracetamol. The SLE was experimentally determined by differential scanning calorimetry. The thermograms obtained revealed that all binary mixtures investigated form eutectic systems. Melting of the initial binary crystalline mixtures and subsequent quenching lead to the formation of CAM for all binary systems and most of the compositions studied. The experimentally obtained liquidus and eutectic temperatures were compared to theoretical predictions using the perturbed-chain statistical associating fluid theory (PC-SAFT) equation of state and conductor-like screening model for real solvents (COSMO-RS), as implemented in the Amsterdam Modeling Suite (COSMO-RS-AMS). On the basis of the obtained results, the ability of these models to predict the phase diagrams for the investigated API-API binary systems was evaluated. Furthermore, the glass transition temperature (Tg) of naproxen (NAP), a compound with a high tendency to recrystallize, whose literature values are considerably scattered, was newly determined by measuring and modeling the Tg values of binary mixtures in which amorphous NAP was stabilized. Based on this analysis, erroneous literature values were identified.

Design of experiments approach on the compaction properties of co-amorphous tablets.

Co-amorphous systems are an evolving strategy to stabilize the amorphous form of a drug molecule with the aim of overcoming its poor water-solubility. With research focussing on the molecular level of co-amorphous systems, little is known about their downstream processing. In this study, tablets of co-amorphous carvedilol and aspartic acid (CAR-ASP) with calcium hydrogen phosphate and croscarmellose sodium as excipients were produced using a compaction simulator. The amorphous form of spray dried CAR-ASP and the subsequently produced tablets was confirmed with XRPD. Over the storage time of 12 weeks, no recrystallization of the amorphous material was observed. A central composite face-centred design with three factors was set up to investigate the interplay of formulation and processing variables with the tablet characteristics elastic work, tensile strength and disintegration time. As a result, increasing the amount of co-amorphous material led to a decrease in elastic work and an increased tensile strength. These effects were beneficial for tablet properties, namely harder tablets and reduced elasticity. Disintegration time was prolonged by amounts of up to 25-30% co-amorphous material, while larger amounts induced faster tablet disintegration. While showing the feasibility of compacting co-amorphous material with calcium hydrogen phosphate, this study also gives insight into how tablet characteristics are affected by co-amorphous material and relevant process parameters.

Characterization of co-amorphous carvedilol-maleic acid system prepared by solvent evaporation.

The aim of this study was to enhance the solubility and stability of the water-insoluble drug carvedilol (CAR) with maleic acid (MLE) to create a co-amorphous system by a solvent evaporation method. Phase diagrams of co-amorphous CAR-MLE, constructed from peak height in the Fourier-transform infrared (FTIR) spectra and the glass transition temperature (Tg) from differential scanning calorimetry (DSC) measurements, revealed that the optimal molar ratio of CAR to MLE was 2:1. The FTIR spectra indicated that the secondary amine-derived peak of CAR and the carboxy group-derived peak of MLE disappeared in the CAR:MLE (2:1) co-amorphous system. DSC measurements showed that the endothermic peaks associated with the melting of CAR and MLE disappeared and a Tg at 43 °C was apparent. Furthermore, the solubility of CAR tested using the shaking flask method for 24 h at 37 °C was 1.2 µg/mL, whereas that of the co-amorphous system was approximately three times higher, at 3.5 µg/mL. Finally, the stability was evaluated by powder- X-ray diffraction at 40 °C; no clear diffraction peaks originating from crystals were observed in the amorphous state until after approximately three months of storage. These results indicate that co-amorphization of CAR with MLE improved the solubility of CAR while maintaining its stability in an amorphous form.

Amorphization of Low Soluble Drug with Amino Acids to Improve Its Therapeutic Efficacy: a State-of-Art-Review.

Low aqueous solubility of drug candidates is an ongoing challenge and pharmaceutical manufacturers pay close attention to amorphization (AMORP) technology to improve the solubility of drugs that dissolve poorly. Amorphous drug typically exhibits much higher apparent solubility than their crystalline form due to high energy state that enable them to produce a supersaturated state in the gastrointestinal tract and thereby improve bioavailability. The stability and augmented solubility in co-amorphous (COA) formulations is influenced by molecular interactions. COA are excellent carriers-based drug delivery systems for biopharmaceutical classification system (BCS) class II and class IV drugs. The three important critical quality attributes, such as co-formability, physical stability, and dissolution performance, are necessary to illustrate the COA systems. New amorphous-stabilized carriers-based fabrication techniques that improve drug loading and degree of AMORP have been the focus of emerging AMORP technology. Numerous low-molecular-weight compounds, particularly amino acids such as glutamic acid, arginine, isoleucine, leucine, valine, alanine, glycine, etc., have been employed as potential co-formers. The review focus on the prevailing drug AMORP strategies used in pharmaceutical research, including in situ AMORP, COA systems, and mesoporous particle-based methods. Moreover, brief characterization techniques and the application of the different amino acids in stabilization and solubility improvements have been related.

Design of a Stable Coamorphous System Using Lactose as an Antiplasticizing Agent for Diphenhydramine Hydrochloride with a Low Glass Transition Temperature.

Coamorphous systems comprising small molecules are emerging as counterparts to polymeric solid dispersions. However, the glass transition temperatures (Tgs) of coamorphous materials are relatively low because of the lack of polymeric carriers with higher Tgs. This study aimed to investigate the applicability of lactose (LAC) as an antiplasticizing coformer to a coamorphous system. Diphenhydramine hydrochloride (DPH) was selected as a model drug (Tg = 16 °C). Differential scanning calorimetry showed a comelting point in addition to a decrease in the neat melting points depending on the composition of the physical mixtures, suggesting that the mixture of DPH-LAC was eutectic. The melting point of the eutectic mixture was calculated according to the Schröder-van Laar equation. The heat of fusion of the eutectic mixture was maximized at a 70:30 molar ratio of DPH to LAC; at this point, the melting peaks of the pure components disappeared. The heat flow profiles following the melting and cooling of DPH-LAC physical mixtures at the ratios from 10:90 to 90:10 showed a single Tg, suggesting the formation of a coamorphous system. Lactose showed a Tg of over 100 °C, and the Tg of DPH increased with the molar ratio of LAC; it was 84 °C at a 10:90 molar ratio of DPH to LAC. The Raman image indicated the formation of a homogeneous dispersion of DPH and LAC in the coamorphous system. Peak shifts in the infrared spectra indicated the presence of intermolecular interactions between the amino group of DPH and the hydroxyl group of LAC. Principal component analysis of the infrared spectra revealed a significant change at the 70:30 molar ratio of DPH to LAC, which was in agreement with the results of the thermal analysis. A stability test at 40 °C revealed rapid crystallization of the supercooled liquid DPH. The coamorphous samples containing 10-50% of LAC remained in an amorphous state for 21 days, and no crystallization was observed for the samples containing >60% of LAC for 28 days. The relatively lower Tg (less than 40 °C) of the coamorphous system containing 10-50% of LAC might have caused crystallization during storage. These findings indicate that LAC, which is a safe and widely used pharmaceutical excipient, can be applied to coamorphous systems as an antiplasticizing coformer.

Co-amorphous Systems of Sinomenine with Platensimycin or Sulfasalazine: Physical Stability and Excipient-Adjusted Release Behavior.

There is strong interest to develop affordable treatments for the infection-associated rheumatoid arthritis (RA). Here, we present a drug-drug co-amorphous strategy against RA and the associated bacterial infection by the preparation and characterization of two co-amorphous systems of sinomenine (SIN) with platensimycin (PTM) or sulfasalazine (SULF), two potent antibiotics. Both of them were comprehensively characterized using powder X-ray diffraction, temperature-modulated differential scanning calorimetry, Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy. The co-amorphous forms of SIN-PTM and SIN-SULF exhibited high Tgs at 139.10 ± 1.0 and 153.3 ± 0.2 °C, respectively. After 6 months of accelerated tests and 1 month of drug-excipient compatibility experiments, two co-amorphous systems displayed satisfactory physical stability. The formation of salt and strong intermolecular interactions between SIN and PTM or SULF, as well as the decreased molecular mobility in co-amorphous systems, may be the intrinsic mechanisms underlying the excellent physical stability of both co-amorphous systems. In dissolution tests, two co-amorphous systems displayed distinct reduced SIN-accumulative releases (below 20% after 6 h of release experiments), which may lead to its poor therapeutic effect. Hence, we demonstrated a controlled release strategy for SIN by the addition of a small percentage of polymers and a small-molecule surfactant to these two co-amorphous samples as convenient drug excipients, which may also be used to improve the unsatisfactory dissolution behaviors of the previously reported SIN co-amorphous systems. Several hydrogen bonding interactions between SIN and PTM or SULF could be identified in NMR experiments in DMSO-d6, which may be underlying reasons of decreased dissolution behaviors of both co-amorphous forms. These drug-drug co-amorphous systems could be a potential strategy for the treatment of infection-associated RA.

Influence of Water on Amorphous Lidocaine.

Water is generally regarded as a universal plasticizer of amorphous drugs or amorphous drug-containing systems. A decrease in glass-transition temperature (Tg) is considered the general result of this plasticizing effect. A recent study exhibits that water can increase the Tg of amorphous prilocaine (PRL) and thus shows an anti-plasticizing effect. The structurally similar drug lidocaine (LID) might show similar interactions with water, and thus an anti-plasticizing effect of water is hypothesized to also occur in amorphous LID. However, the influence of water on the Tg of LID cannot be determined directly due to the very low stability of LID in the amorphous form. It is possible to predict the Tg of LID from a co-amorphous system of PRL-LID using the Gordon-Taylor equation. Interactions were observed between PRL and LID based on the deviations between the experimental Tgs and the Tgs calculated by the conventional use of the Gordon-Taylor equation. A modified use of the Gordon-Taylor equation was applied using the optimal co-amorphous system as a separate component and the excess drug as the other component. The predicted Tg of fully hydrated LID could thus be determined and was found to be increased by 0.9 ± 0.7 K compared with the Tg of water-free amorphous LID. It could be shown that water exhibited a small anti-plasticizing effect on LID.