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AbstractIntroduction Strategies to address the problem of poorly water-soluble drugs encompass the conversion of a crystalline drug into an amorphous form to promote its apparent solubility and dissolution. Co-amorphous systems (CAMs) incorporate low molecular mass molecules (co-formers), which are mixed with the drug to form one single phase [1,2]. The aim of this study is to understand the capability of different co-formers (amino, carboxylic and sulphonic acids), in the production of CAMs with olanzapine by ball milling, solvent evaporation and quench cooling.Materials and methods Mixtures (2 g) of olanzapine (OLZ) and each co-former [l-aspartate (ASP); l-tryptophan (TRY); l-arginine (ARG); l-proline (PRO); citric acid (CIT); tartaric acid (TAR); oxalic acid (OXA); saccharine (SAC); potassium acessulfame (ACE); cyclamic acid (CYC)] in 1:1 molar ratios were submitted to ball milling (BM), solvent evaporation (SE) and quench cooling (QC). CAMs were evaluated for the OLZ solubility increase, co-formability and storage stability over time, by differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD) and Fourier-transform infra-red spectroscopy (FTIR).Results The BM technique presented the most promising results followed by QC and SE (Table 1), since more CAMs were produced. All the sulphonic acids (SAC, CYC and ACE) formed CAMs regardless of the technique used, presenting complete amorphization probably due to their higher ability to produce intermolecular interactions, like hydrogen-bonding, thus increasing the stability of CAMs (more than 8 weeks at 25 °C/11 and 53% RH). Conversely, amino acids were the least efficient in producing CAMs. Crystalline OLZ presented low solubility (40.1 mg/L) in water and a general increase in the solubility of the CAMs was observed. Carboxylic acids (TAR, CIT, OXA) achieved the biggest increase (up to 269 times, BM with TART) followed by sulphonic acids (up to 199 times, SE with SAC), unveiling the possibility of improved dissolution profiles and bioavailability. Discussion and conclusions: The study has shown the possibility of converting a crystalline drug into an amorphous entity, particularly when in presence of co-formers which stabilise the amorphous structures formed. In fact, with sulphonic acids, both SE and BM, achieved complete amorphization and successfully stabilised the CAMs obtained. Due to the noteworthy increase in solubility, resulting from co-amorphization, this technique is considered to be adequate to process active compounds with poor water solubility, such as OLZ.Table 1. Comparison of the of co-amorphization ability using different techniques and co-formers.[Table: see text]aIncomplete amorphization; bcomplete amorphization.

AbstractIntroduction The production of amorphous and co-amorphous (CAM) materials has been used as a procedure to overcome the poor water solubility shown by most of the drugs currently under development [1]. Ball milling has been considered to convert the crystalline state of a substance into its amorphous counterpart [2,3]. At present, the impact of the initial polymorphic form of a drug substance on its final amorphous state upon milling, has not been clearly studied. This work aims to compare the co-amorphization efficiency of two different polymorphic forms of olanzapine (OLZ; a BCS class II drug) using saccharin (SAC) as a co-former.Materials and methods OLZ (forms I and II) were the starting polymorphic forms to be milled with SAC (2:1 molar ratio). OLZ form I was used as received while OLZ form II was obtained from crystallisation of OLZ in dichloromethane. Ball milling was performed using 2.5 g of 3.0 mm Ø balls, for 2 h. The conversion of the crystalline states into the amorphous counterpart was monitored by calorimetry (DSC) and diffractometry (XRPD).Results The thermograms and the diffractograms obtained (Figure 1) have shown a clear difference between the final products of the two polymorphic forms of OLZ. XRPD peaks were less intense for OLZ form II and most representative of SAC, indicating that OLZ was indeed mostly converted into the amorphous state. On the other hand, when OLZ form I was the starting material, a richer diffractogram resulted, suggesting that a crystalline fraction of OLZ remained in the particles’ network of the final product, a feature also confirmed by DSC. Discussion and conclusions: Since OLZ form II has a higher thermodynamic energy than form I, it is not surprising that the former exhibits better amorphization ability. Thus, it is expected that either an increase on milling time, or milling speed, would enhance the co-amorphization of OLZ form I with SAC.[Figure: see text]

AbstractIntroduction A large number of active pharmaceutical compounds currently under development are poorly water soluble, which can limit their bioavailability and results in formulation challenges [1]. Co-amorphous systems (CAMs) are known to increase the apparent solubility and dissolution rate of drugs [1,2]. To date, sulphonic acids have never investigated as possible co-formers for Olanzapine (OLZ; a BSC class II drug) and, thus, the aim of this work is to evaluate their potential on the formation of stable CAMs.Materials and methods OLZ was used as model drug. Saccharin (SAC), cyclamic acid (CA), acesulfame (ACE; obtained by neutralisation of potassium acesulfame) and their salts, sodium saccharin, sodium cyclamate and potassium acesulfame, respectively, were used as co-formers. Mixtures (2 g) of OLZ and each co-former, in molar ratios 1:1, were submitted to milling, solvent evaporation (SE) and quench cooling. Samples were characterised by differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), Fourier-transform infra-red spectroscopy (FTIR) and cooling/heating stage microscopy. Solubility assessment, powder dissolution rate and stability studies were also performed.Results SAC, CA and ACE demonstrated to be successful co-formers in the production and stabilisation of OLZ-CAMs obtained by the three different techniques, presenting a single glass transition temperature (Tg) in thermograms and a typical halo in XRPD diffractograms. None of the salts were capable of forming a CAM, resulting in phase separation and absence of Tg events. Microscopical analysis supported DSC data and provided images of the CAMs recrystallization. Band shifts and broadening of the CAMs FTIR spectra suggest an intermolecular interaction between the N–H group in OLZ and the C = O group in SAC and ACE and the O-H group in CA. Solubility of OLZ was significantly increased (up to 199 times) when produced by SE with SAC. Dissolution rate was also increased for all the CAMs produced. SAC and CA successfully stabilised the CAMs produced, for more than 8 weeks at 25 °C/11, 53 and 75% RH and at 25 °C/11 and 53% RH, respectively.Discussion and conclusions In this study OLZ was successfully amorphized using the neutral forms of the sulphonic acids. The impossibility of the salts to form a CAM is in agreement with the FTIR results, since the groups responsible for the molecular interaction with OLZ are unavailable in these molecules due to their negative charge. SE proved to be the best technique to produce CAMs with the different co-formers, resulting in the highest increase in solubility. SAC has shown to be the best co-former, with the highest solubility and stability over time, under higher relative humidity. Moreover, the increased dissolution rate of the CAMs suggests improved bioavailability of OLZ, a feature with therapeutic impact, which should be confirmed in vivo.

AbstractIntroduction Amorphous and co-amorphous (CAM) materials have recently been used to improve oral bioavailability of drugs, by enhancing water solubility and dissolution rate from solid dosage forms [1,2]. However, stress conditions imposed on amorphous systems during production of such dosage forms (e.g. pressure upon tableting), can revert the drug back into the less soluble crystalline form [3]. This work thus presents a methodology to monitor and quantify the fraction of amorphous olanzapine (OLZ) remaining in immediate release OLZ tablets (Table 1).Table 1. Predicted fraction of amorphous OLZ, by NIR and FTIR spectroscopies, in tablets prepared with the co-amorphous system.[Table: see text]Materials and methods Near infra-red (NIR, 9000–4000 cm−1) and Fourier-transform infra-red (FTIR, 4000–500 cm−1) techniques were used to quantify the fraction of co-amorphous OLZ (30%) with saccharin (SAC; 18%) in formulations containing also calcium phosphate (27%), microcrystalline cellulose (20%) and povidone (5%). Tablets (250 mg) were obtained using a universal testing machine fit with circular punches (7.5 mm Ø), at a constant compression rate of 10 mm/min (n = 5); different compression forces (8 and 25 kN) and dwell times (DT; 0 and 20 min) were considered. Evaluation of the impact of the compression conditions on the recrystallization of OLZ from a co-amorphous system was based on a computational model.Results Using a 2nd derivative filter to process both NIR and FTIR spectra, the quantification of amorphous olanzapine was possible with a root mean square error of calibration and prediction above 2% (Figure 1). The method was further applied to evaluate the stability of co-amorphous systems after tableting, revealing that no significant recrystallization occurred, i.e. the co-amorphous were stable under the stress conditions applied. Discussion and conclusions: The use of NIR and FTIR resulted in high correlation between the predicted values and the expected ones, thus enabling these spectroscopic techniques to be used to monitor the conversion of amorphous into crystalline OLZ forms and thus estimate the impact on drug bioavailability. Understanding of the conversion kinetics will ultimately allow anticipation of the time for complete recrystallization. The model developed has also demonstrated that tablets produced were stable, since no recrystallization was observed.[Figure: see text]