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Successful oral delivery of liposomes requires formulations designed to withstand harsh gastrointestinal conditions, e.g., by converting to solid-state followed by loading into gastro-resistant delivery devices. The hypothesis was that the use of dextran-trehalose mixtures for spray drying would improve the rehydration kinetics of dried liposomes. The objectives were to determine the protective capacity of trehalose-dextran dehydration precursors and to increase the concentration of liposomes in the dry formulation volume. The study successfully demonstrated that 8.5% dextran combined with 76.5% trehalose protected CAF®04 liposomes during drying, with the liposome content maintained at 15% of the dry powder. Accordingly, the rehydration kinetics were slightly improved in formulations containing up to 8.5% dextran in the dry powder volume. Additionally, a 2.4-fold increase in lipid concentration (3 mM vs 7.245 mM) was achieved for spray dried CAF®04 liposomes. Ultimately, this study demonstrates the significance of trehalose as a primary carrier during spray drying of CAF®04 liposomes and highlights the advantage of incorporating small amounts of dextran to tune rehydration kinetics of spray-dried liposomes., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AL, GKP, STS are employed at Statens Serum Institut, which is a non-profit government research facility and holds patents on the CAF®-based adjuvants. All other authors declare that there are no competing interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The encapsulation of drugs within mesoporous silica (MS) has for several years been a subject of research. Previous studies proposed that drug loadings up to the monomolecular loading capacity (MLC) are the optimal choice for maintaining the drug in an amorphous form, whereas filling the pores above the monolayer and up to the pore filling capacity (PFC) may introduce some physical instabilities. The aim of this study was to assess the effect of drug loading in MS-based amorphous formulations on the stability of the amorphous form of the drug as well as the dissolution. In particular, the following drug loadings were investigated: below MLC, at MLC, between MLC and PFC and at PFC. The drug-loaded MS formulations were analyzed directly after preparation and after 18 months of storage under accelerated conditions (40 °C in both dry and humid conditions). The MLC and PFC for the drug celecoxib (CEL) on the MS ParteckSLC500 (SLC) were determined at 33.5 wt.% and 48.4 wt.%, respectively. This study found that SLC can effectively preserve the amorphous form of the drug for 18 months, provided that the loading is below the PFC (<48.4 wt.%) and no humidity is present. On the other hand, drug loading at the PFC showed recrystallization even when stored under dry conditions. Under humid conditions, however, all samples, regardless of drug loading, showed recrystallization upon storage. In terms of dissolution, all freshly prepared formulations showed supersaturation. For drug loadings below PFC, a degree of supersaturation (DS) around 15 was measured before precipitation was observed. For drug loadings at PFC, the DS was found to be lower and only 6-times compared to the crystalline solubility. Lastly, for those samples that remained amorphous during storage for 18 months, the release profiles were found to be the same as the freshly loaded samples, with similar C max , T max and dissolution rate.

Supersaturating drug delivery systems such as solid dispersions of a drug in a polymer are frequently used in pharmaceutical development to enable oral delivery of poorly soluble drugs. In this study, the influence of the concentration and molecular weight of polyvinylpyrrolidone (PVP) on the precipitation inhibition of the poorly soluble drugs albendazole, ketoconazole and tadalafil is investigated to expand the understanding of the mechanism of PVP as a polymeric precipitation inhibitor. A three-level full-factorial design was used to delineate the influence of polymer concentration and viscosity of the dissolution medium on precipitation inhibition. Solutions of PVP K15, K30, K60 or K120 at concentrations of 0.1, 0.5 and 1% ( w / v ), as well as isoviscous solutions of PVP of increasing molecular weight, were prepared. Supersaturation of the three model drugs was induced by the use of a solvent-shift method. Precipitation of the three model drugs from supersaturated solutions in the absence and presence of polymer was investigated by the use of a solvent-shift method. Time-concentration profiles of the respective drugs in the absence and presence of polymer pre-dissolved in the dissolution medium were obtained by the use of a μDISS Profiler™ to determine the onset of nucleation and the precipitation rate. Multiple linear regression was used to evaluate the hypothesis that precipitation inhibition is influenced by the PVP concentration (i.e., the number of repeat units of the polymer) and the medium viscosity of the polymer for the three model drugs. This study showed that an increased concentration of PVP (i.e., an increased concentration of the PVP repeat units, independent of the molecular weight of the polymer) in solution increased the onset of nucleation and decreased the precipitation rate of the respective drugs during supersaturation, which can be explained by an increase in molecular interactions between the drug and polymer with increasing concentrations of polymer. In contrast, the medium viscosity had no significant influence on the onset of the nucleation and precipitation rate of the drugs, which can be explained by solution viscosity having a negligible effect on the rate of drug diffusion from bulk solution to the crystal nuclei. In conclusion, the precipitation inhibition of the respective drugs is influenced by the concentration of PVP, i.e., by molecular interactions between the drug and polymer. In contrast, the molecular mobility of the drug in solution, i.e., the medium viscosity, has no influence on the precipitation inhibition of the drugs.

In this study, a new method to determine the solubility of crystalline drugs in (amorphous) polymers is proposed. The method utilizes annealing of supersaturated amorphous solid dispersions to achieve equilibrium between dissolved and recrystallized drug. By measuring the enthalpy of melting and mixing (H m+mix ) of the recrystallized drug, the equilibrium solubility of the drug in the polymer at the annealing temperature is determined. The equilibrium solubilities at these elevated temperatures were used to extrapolate to room temperature using the Flory-Huggins model. The new H m+mix method showed solubility predictions in line with the melting point depression (MPD) and recrystallization (RC) methods for indomethacin (IMC) -polyvinylpyrrolidone (PVP). For IMC-hydroxypropyl methylcellulose (HPMC), the MPD method plateaued rapidly, leaving only one usable data point. The RC method showed large variations in the solubility predictions possibly due to a narrow glass transition temperature (T g ) window or inaccurate T g determination. In contrast, the new H m+mix method showed robust solubility prediction over the entire annealing temperature range with low variation and narrow error margins after extrapolation for both drug-polymer systems. The new H m+mix method was able to accurately determine the drug-polymer solubility of IMC-HPMC, showing promise as a new tool to determine the solubility of problematic drug-polymer systems., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

In the current study, the concept of multiparticulate drug delivery systems (MDDS) was applied to tablets intended for the amorphisation of supersaturated granular ASDs in situ, i.e. amorphisation within the final dosage form by microwave irradiation. The MDDS concept was hypothesised to ensure geometric and structural stability of the dosage form and to improve the in vitro disintegration and dissolution characteristics. Granules were prepared in two sizes (small and large) containing the crystalline drug celecoxib (CCX) and polyvinylpyrrolidone/vinyl acetate copolymer (PVP/VA) at a 50 % w/w drug load as well as sodium dihydrogen phosphate monohydrate as the microwave absorbing excipient. The granules were subsequently embedded in an extra-granular tablet phase composed of either the filler microcrystalline cellulose (MCC) or mannitol (MAN), as well as the disintegrant crospovidone and the lubricant magnesium stearate. The tensile strength and disintegration time were investigated prior to and after 10 min of microwave irradiation (800 and 1000 W) and the formed ASDs were characterised by X-ray powder diffraction and modulated differential scanning calorimetry. Additionally, the internal structure was elucidated by X-ray micro-Computed Tomography (XµCT) and, finally, the dissolution performance of selected tablets was investigated. The MDDS tablets displayed no geometrical changes after microwave irradiation, however, the tensile strength and disintegration time generally increased. Complete amorphisation of CCX was achieved only for the MCC-based tablets at a power input of 1000 W, while MAN-based tablets displayed partial amorphisation independent of power input. The complete amorphisation of CCX was associated with the fusion of individual ASD granules within the tablets, which negatively impacted the subsequent disintegration and dissolution performance. For these tablets, supersaturation was only observed after 60 min. On the other hand, the partially amorphised MDDS tablets displayed complete disintegration during the dissolution experiments, resulting in a fast onset of supersaturation within 5 min and an approx. 3.5-fold degree of supersaturation within the experimental timeframe (3 h). Overall, the MDDS concept was shown to potentially be a feasible dosage form for in situ amorphisation, however, there is still room for improvement to obtain a both fully amorphous and disintegrating system., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

This study investigated the ability of in situ amorphisation using microwave irradiation in order to prepare highly supersaturated ASDs, i.e. ASDs with drug loads higher than the saturation solubility in the polymer at ambient temperature. For this purpose, compacts containing the crystalline drug celecoxib (CCX) and polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-vinyl acetate copolymer (PVP/VA), or polyvinyl acetate (PVAc), were prepared at drug loads between 30 and 90 % w/w. Sodium dihydrogen phosphate (NaH 2 PO 4 ) monohydrate was included in all compacts, as a source of water, to facilitate the dielectric heating of the compacts upon dehydration during microwave irradiation. After processing, the samples were analysed towards their solid state using X-ray powder diffraction (XRPD) and modulated differential scanning calorimetry (mDSC). Complete amorphisation of CCX was achieved across all the investigated polymers and with a maximal drug load of 90, 80, and 50 % w/w in PVP, PVP/VA, and PVAc, respectively. These drug loads corresponded to a 2.3-, 2.4-, and 10.0-fold supersaturation in the investigated polymers at ambient temperature. However, dissolution experiments with the in situ prepared ASDs in fasted state simulated intestinal fluid (FaSSIF), showed a lower initial drug release (0-2 h) compared to equivalent physical mixtures of crystalline CCX and polymers or crystalline CCX alone. The lower drug release rate was explained by the fusion of individual drug and polymer particles during microwave irradiation and, subsequently, a lack of disintegration of the monolithic ASDs. Nevertheless, supersaturation of CCX in FaSSIF was achieved with the in situ amorphised ASDs with PVP and PVP/VA, albeit only after 3-24 h. Overall, the present study confirmed that it is feasible to prepare supersaturated ASDs in situ. However, in the current experimental setup, the monolithic nature of the resulting ASDs is considered a limiting factor in the practical applicability of this preparation method, due to limited disintegration and the associated negative effect on the drug release., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Korbinian Loebmann reports financial support was provided by Independent Research Fund Denmark., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Microwave-induced in situ amorphization is an emerging technology to tackle the persistent stability issue of amorphous solid dispersions (ASDs) during manufacture and storage. The aim of this study was to introduce new effective polymeric carriers with diverse properties to microwave-induced in situ amorphization and to better understand their functions in relation to the final dissolution performance of microwaved tablets. Tablets composed of indomethacin (IND) and different polymers were compacted, stored at 75% relative humidity for at least 1 week and microwaved at 1000 W to induce amorphization. A series of polymers, polyvinylpyrrolidone/vinyl acetate copolymers (PVP/VA) of different monomer weight ratios displaying varyingproperties in functional groupratio, hygroscopicity, molecular weight (M w ), and glass transition temperature (T g ) of the polymer were used as model carriers. The results suggested that more than 90% of IND was amorphized after 20 mins microwaving in all 20% (w/w) drug loaded tablets except for IND:PVAc tablets presenting approx. 36% residual crystallinity. Among them, tablets composed of PVP/VA I-335 and PVP K30 achieved complete in situ amorphization upon microwaving. Further analysis indicated that the influencing factors, polymer M w and T g of moisture-plasticized polymer, played a major role in microwave-induced in situ amorphization. In in vitro dissolution study, ASDs containing PVP/VA I-535 with moderate hydrophilicity and 0.96 ± 1.92% IND residual crystallinity showed the most rapid and complete drug release among all formulations, presenting the most promising dissolution performance. Further study on the chemical stability of such formulation showed a statistically insignificant decrease of drug content after pre-conditioning and microwaving (P = 0.288 > 0.05)., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The use of a mixture of polyethylene glycol (PEG) and polyvinylpyrrolidone (PVP) was investigated for microwave-induced in situ amorphization of celecoxib (CCX) inside compacts. Such amorphization requires the presence of a dipolar excipient in the formulation to ensure heating of the compact by absorption of the microwaves. Previously, the hygroscopic nature of PVP was exploited for this purpose. By exposing PVP-based compacts for set time intervals at defined relative humidity, controlled water sorption into the compacts was achieved. In the present study, PEG was proposed as the microwave absorbing excipient instead of water, to avoid the water sorption step. However, it was found that PEG alone melted upon exposure to microwave radiation and caused the compact to deform. Furthermore, CCX was found to recrystallize upon cooling in PEG-based formulations. Hence, a mixture of PEG and PVP was used, where the presence of PVP preserved the physical shape of the compact, and the physical state of the amorphous solid dispersion. To study the impact of the polymer mixture, different compact compositions of CCX, PEG and PVP were prepared. When exposing the compacts to microwave radiation, it was found that the PEG:PVP ratio was critical for in situ amorphization and that complete amorphization was only achieved above a certain temperature threshold., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Amorphisation within the final dosage form, i.e. in situ amorphisation, seeks to circumvent the potential stability issues associated with poorly soluble drugs in amorphous solid dispersions (ASDs). Microwave irradiation has previously been shown to enable in situ preparation of ASDs, when a high amount of microwave absorbing water was introduced into the final dosage form by conditioning at high relative humidity. In this study, an alternative to this conditioning step was investigated by introducing crystal water in form of sodium dihydrogen phosphate (NaH 2 PO 4 ) di-, and monohydrate, in compacts prepared with 30 % w/w celecoxib (CCX) in polyvinylpyrrolidone K12 (PVP). As controls, compacts prepared with NaH 2 PO 4 anhydrate and without NaH 2 PO 4 were included in the study. The quantification of amorphous CCX after microwave irradiation showed an increase in CCX amorphicity for compacts containing NaH 2 PO 4 di-, and monohydrate with increasing irradiation time. Complete amorphisation of CCX in compacts containing NaH 2 PO 4  di-, and monohydrate was observed after 6 min, while no appreciable amorphisation was observed for the control compacts containing NaH 2 PO 4 anhydrate and without NaH 2 PO 4 . Modulated differential scanning calorimetric analysis revealed that a homogenous ASD was formed after 12 min and 6 min for compacts containing NaH 2 PO 4 di-, and monohydrate, respectively. Thermal gravimetric analysis indicated that NaH 2 PO 4 monohydrate showed higher dehydration rates compared to the dihydrate, which in turn resulted in higher compact temperatures, and overall increased the rate of amorphisation and reduced the microwave irradiation time necessary to achieve a homogenous ASD. The present results confirmed the suitability of NaH 2 PO 4 di- and monohydrate as alternative sources of water, the primary microwave absorbing material, for in situ microwave amorphisation. The use of crystalline hydrates as water reservoirs for in situ amorphisation circumvents the time-consuming and highly impractical conditioning step previously reported in order to achieve complete amorphisation. Additionally, it allows for easier and more accurate adjustment of the compacts water content, which directly affects the temperature reached during microwave irradiation, and thus, the rate of amorphisation., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Laser radiation has been shown to be a promising approach for in situ amorphization, i.e., drug amorphization inside the final dosage form. Upon exposure to laser radiation, elevated temperatures in the compacts are obtained. At temperatures above the glass transition temperature ( T g ) of the polymer, the drug dissolves into the mobile polymer. Hence, the dissolution kinetics are dependent on the viscosity of the polymer, indirectly determined by the molecular weight ( M w ) of the polymer, the solubility of the drug in the polymer, the particle size of the drug and the molecular size of the drug. Using compacts containing 30 wt% of the drug celecoxib (CCX), 69.25 wt% of three different M w of polyvinylpyrrolidone (PVP: PVP12, PVP17 or PVP25), 0.25 wt% plasmonic nanoaggregates (PNs) and 0.5 wt% lubricant, the effect of the polymer M w on the dissolution kinetics upon exposure to laser radiation was investigated. Furthermore, the effect of the model drug on the dissolution kinetics was investigated using compacts containing 30 wt% of three different drugs (CCX, indomethacin (IND) and naproxen (NAP)), 69.25 wt% PVP12, 0.25 wt% PN and 0.5 wt% lubricant. In perfect correlation to the Noyes-Whitney equation, this study showed that the use of PVP with the lowest viscosity, i.e., the lowest M w (here PVP12), led to the fastest rate of amorphization compared to PVP17 and PVP25. Furthermore, NAP showed the fastest rate of amorphization, followed by IND and CCX in PVP12 due to its high solubility and small molecular size.

In this study, laser-induced in situ amorphization (i.e., amorphization inside the final dosage form) of the model drug celecoxib (CCX) with six different polymers was investigated. The drug-polymer combinations were studied with regard to the influence of (i) the physicochemical properties of the polymer, e.g., the glass transition temperature ( T g ) and (ii) the drug-polymer solubility on the rate and degree of in situ drug amorphization. Compacts were prepared containing 30 wt% CCX, 69.25 wt% polymer, 0.5 wt% lubricant, and 0.25 wt% plasmonic nanoparticles (PNs) and exposed to near-infrared laser radiation. Upon exposure to laser radiation, the PNs generated heat, which allowed drug dissolution into the polymer at temperatures above its T g , yielding an amorphous solid dispersion. It was found that in situ drug amorphization was possible for drug-polymer combinations, where the temperature reached during exposure to laser radiation was above the onset temperature for a dissolution process of the drug into the polymer, i.e., T DStart . The findings of this study showed that the concept of laser-induced in situ drug amorphization is applicable to a range of polymers if the drug is soluble in the polymer and temperatures during the process are above T DStart .

Microwave-induced in situ amorphization of a drug into a polymeric amorphous solid dispersion (ASD) has been suggested to follow a dissolution process of the drug into the polymeric network, at temperatures above the glass transition temperature ( T g ) of the polymer. Thus, increasing the compact temperature, above the T g of the polymer, is expected to increase the rate of drug dissolution in the mobile polymer, i.e., the rate of amorphization, in a direct proportional fashion. To test this hypothesis, the present study aimed at establishing a linear correlation between the compact temperature and the rate of drug amorphization using celecoxib (CCX) and the polymers polyvinylpyrrolidone (PVP) 12 and PVP17 as the model systems. Water sorbed into the drug-polymer compacts during 2 weeks of storage at 75% relative humidity was used as the dielectric heating source for the present drug amorphization process, and therefore directly affected the compact temperature during exposure to microwave radiation; the loss of water during heating was also studied. For this, compacts prepared with 30 wt% CCX, 69.5 wt% PVP12 or PVP17 and 0.5 wt% magnesium stearate (lubricant) were conditioned to have a final water content of approx. 20 wt%. The conditioned compacts were exposed to microwave radiation for 10 min at variable power outputs to achieve different compact temperatures. For compacts containing CCX in both PVP12 and PVP17, a linear correlation was established between the measured compact end temperature and the rate of drug amorphization during 10 min of exposure to microwave radiation. For compacts containing CCX in PVP12, a fully amorphous ASD was obtained after 10 min of exposure to microwave radiation with a measured compact end temperature of 71 °C. For compacts containing CCX in PVP17, it was not possible to obtain a fully amorphous ASD. The reason for this is most likely that a fast evaporation of the sorbed water increased the T g of the conditioned drug-polymer compacts to temperatures above the highest reachable compact temperature during exposure to microwave radiation in the utilized experimental setup. Supporting this conclusion, evaporation of the sorbed water was observed to be faster for compacts containing PVP17 compared to compacts containing PVP12.

Poor aqueous drug solubility represents a major challenge in oral drug delivery. A novel approach to overcome this challenge is drug amorphization inside a tablet, that is, on-demand drug amorphization. The amorphous form is a thermodynamically instable, disordered solid-state with increased dissolution rate and solubility compared to its crystalline counterpart. During on-demand drug amorphization, the drug molecularly disperses into a polymer to form an amorphous solid at elevated temperatures inside a tablet. This study investigates, for the first time, the utilization of photothermal plasmonic nanoparticles for on-demand drug amorphization as a new pharmaceutical application. For this, near-IR photothermal plasmonic nanoparticles were tableted together with a crystalline drug (celecoxib) and a polymer (polyvinylpyrrolidone). The tablets were subjected to a near-IR laser at different intensities and durations to study the rate of drug amorphization under each condition. During laser irradiation, the plasmonic nanoparticles homogeneously heated the tablet. The temperature was directly related to the rate and degree of amorphization. Exposure times as low as 180 s at 1.12 W cm -2 laser intensity with only 0.25 wt % plasmonic nanoparticles and up to 50 wt % drug load resulted in complete drug amorphization. Therefore, near-IR photothermal plasmonic nanoparticles are promising excipients for on-demand drug amorphization with laser irradiation.

Microwave-induced in situ amorphization is a promising approach to circumvent stability and manufacturing issues associated with amorphous solid dispersions (ASD). Using in situ amorphization, the crystalline state of the drug is converted into its amorphous form inside the dosage form, e.g. a compact, upon exposure to microwave radiation. The study aimed to investigate the feasibility of using glycerol as an enabling excipient in compacts prepared from mixtures of indomethacin and Soluplus®. Additionally, the possibility to form a supersaturated ASD upon exposure to microwave radiation due to elevated temperatures was investigated. It was found that glycerol i) acts as a dielectric heating source absorbing the microwaves, ii) plasticizes the polymer Soluplus® and iii) increases the solubility of the drug indomethacin in the polymer Soluplus®. Additionally, it was found that fully amorphous ASDs could be achieved with drug loadings below -, and slightly above the saturation solubility of indomethacin in the Soluplus®/glycerol mixtures, after exposure to 20 min of microwave radiation. Hence, glycerol was a feasible excipient for the microwave-induced in situ amorphization and allowed the preparation of a, at room temperature, supersaturated ASD, due to the elevated temperatures obtained during exposure to microwave radiation., (Copyright © 2020 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Microwaved-induced in situ amorphization of a drug in a polymer has been suggested to follow a dissolution process, with the drug dissolving into the mobile polymer at temperatures above the glass transition temperature ( T g ) of the polymer. Thus, based on the Noyes-Whitney and the Stoke-Einstein equations, the temperature and the viscosity are expected to directly impact the rate and degree of drug amorphization. By investigating two different viscosity grades of polyethylene glycol (PEG), i.e., PEG 3000 and PEG 4000, and controlling the temperature of the microwave oven, it was possible to study the influence of both, temperature and viscosity, on the in situ amorphization of the model drug celecoxib (CCX) during exposure to microwave radiation. In this study, compacts containing 30 wt% CCX, 69 wt% PEG 3000 or PEG 4000 and 1 wt% lubricant (magnesium stearate) were exposed to microwave radiation at ( i ) a target temperature, or ( ii ) a target viscosity. It was found that at the target temperature, compacts containing PEG 3000 displayed a faster rate of amorphization as compared to compacts containing PEG 4000, due to the lower viscosity of PEG 3000 compared to PEG 4000. Furthermore, at the target viscosity, which was achieved by setting different temperatures for compacts containing PEG 3000 and PEG 4000, respectively, the compacts containing PEG 3000 displayed a slower rate of amorphization, due to a lower target temperature, than compacts containing PEG 4000. In conclusion, with lower viscosity of the polymer, at temperatures above its T g , and with higher temperatures, both increasing the diffusion coefficient of the drug into the polymer, the rate of amorphization was increased allowing a faster in situ amorphization during exposure to microwave radiation. Hereby, the theory that the microwave-induced in situ amorphization process can be described as a dissolution process of the drug into the polymer, at temperatures above the T g , is further strengthened.

In this study, the putative correlation between the molecular mobility of a polymer and the ball milling drug amorphization kinetics (i.e., time to reach full drug amorphization, t a ) was studied using different grades of dextran (Dex) and polyvinylpyrrolidone (PVP) and the two model drugs indomethacin (IND) and chloramphenicol (CAP). In general, IND had lower t a values than CAP, indicating that IND amorphized faster than CAP in the presence of the polymers. In addition, an increase in polymer molecular weight (M w ) also led to an increase in t a for all systems investigated up to a critical M w for each polymer, which was in line with an increase of the glass transition temperature (T g ) up to the critical M w of each polymer. Hence, the increase in t a seemed to correlate well with the T g /M w of the polymers, which indicates that the polymers' molecular mobility had an influence on the drug amorphization kinetics during ball milling.

In this study, the impact of drug and polymer particle size on the in situ amorphization using microwave irradiation at a frequency of 2.45 GHz were investigated. Using ball milling and sieve fractioning, the crystalline drug celecoxib (CCX) and the polymer polyvinylpyrrolidone (PVP) were divided into two particle size fractions, i.e. small (<71 µm) and large (>71 µm) particles. Subsequently, compacts containing a drug load of 30% (w/w) crystalline CCX in PVP were prepared and subjected to microwave radiation for an accumulated duration of 600 sec in intervals of 60 sec as well as continuously for 600 sec. It was found that the compacts containing small CCX particles displayed faster rates of amorphization and a higher degree of amorphization during microwave irradiation as compared to the compacts containing large CCX particles. For compacts with small CCX particles, interval exposure to microwave radiation resulted in a maximum degree of amorphization of 24%, whilst a fully amorphous solid dispersion (100%) was achieved after 600 sec of continuous exposure to microwave radiation. By monitoring the temperature in the core of the compacts during exposure to microwave radiation using a fiber optic temperature probe, it was found that the total exposure time above the glass transition temperature (T g ) was shorter for the interval exposure method compared to continuous exposure to microwave radiation. Therefore, it is proposed that the in situ formation of an amorphous solid dispersion is governed by the dissolution of drug into the polymer, which most likely is accelerated above the T g of the compacts. Hence, prolonging the exposure time above the T g , and increasing the surface area of the drug by particle size reduction will increase the dissolution rate and thus, rate and degree of amorphization of CCX during exposure to microwave radiation., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The aim of the study was to investigate the suitability of a convection oven to induce in situ amorphization. The study was conducted using microwave radiation-induced in situ amorphization as reference, as it has recently been shown to enable the preparation of a fully (100%) amorphous solid dispersion of celecoxib (CCX) in polyvinylpyrrolidone (PVP) after 10 min of continuous microwaving. For comparison, the experimental setup of the microwave-induced method was mimicked for the convection-induced method. Compacts containing crystalline CCX and PVP were prepared and either pre-conditioned at 75% relative humidity or kept dry to investigate the effect of sorbed water on the amorphization kinetics. Subsequently, the compacts were heated for 5, 10, 15, 20, or 30 min in the convection oven at 100 °C. The degree of amorphization of CCX in the compacts was subsequently quantified using transmission Raman spectroscopy. Using the convection oven, the maximum degree of amorphization achieved was 96.1% ± 2.1% ( n = 3) for the conditioned compacts after 30 min of heating and 14.3% ± 1.4% ( n = 3) for the dry compacts after 20 min of heating, respectively. Based on the results from the convection and the microwave oven, it was found that the sorbed water acts as a plasticizer in the conditioned compacts (i.e., increasing molecular mobility), which is advantageous for in situ amorphization in both methods. Since the underlying mechanism of heating between the convection oven and microwave oven differs, it was found that convection-induced in situ amorphization is inferior to microwave radiation-induced in situ amorphization in terms of amorphization kinetics with the present experimental setup.

In this study, a method is described to determine the monolayer loading capacity (MLC) of the drugs naproxen and ibuprofen, both having high recrystallization tendencies, in mesoporous silica (MS), a well known carrier that is able to stabilize the amorphous form of a drug. The stabilization has been suggested to be due to direct absorption of the drug molecules onto the MS surface, i.e. the drug monolayer. In addition, drug that is not in direct contact with MS surface can fill the pores up to its pore filling capacity (PFC) and is potentially stabilized by confinement due to the pore size being smaller than a crystal nuclei. For drugs with high recrystallization tendencies, any drug outside the pores crystallizes due to its poor physical stability. The drug monolayer does not contribute to the glass transition temperature ( T g ) in the DSC, however, the confined amorphous drug above MLC has a T g and the heat capacity (Δ C p ) over the T g increases with an increasing fraction of confined amorphous drug. Hence, several drug loading values above the MLC were investigated towards the presence of a T g and Δ C p using differential scanning calorimetry (DSC). A linear correlation between the amount of confined amorphous drug and its Δ C p was identified for the mixtures between the MLC and PFC. By subsequent extrapolation to zero Δ C p the experimental MLC could be determined. Using theoretical density functional theory (DFT) and ab initio Molecular Dynamics (AIMD), the binding energies for the monolayer suggested that the monolayer in fact is thermodynamically more favorable than the crystalline form, whereas the confined amorphous form is thermodynamically less favorable. Consequently, a physical stability study showed that the confined amorphous drugs above the MLC were thermodynamically unstable and consequently flowing out of the pores in order to crystallize, whereas the monolayer remained physically stable.

In this study, the influence of the mesoporous silica (MS) textural properties (surface area, pore diameter, and pore volume) on drug loading capacity (monomolecular loading capacity and pore filling capacity) was investigated theoretically and experimentally using a thermoanalytical method. The loading capacities of three model drugs (celecoxib, cinnarizine, and paracetamol) were determined in five different MS grades of Sylysia® with identical chemical composition, but varying surface area, pore diameter and pore volume. The experimentally determined loading capacities were compared to theoretical loading capacities, calculated based on the surface area and amorphous density of the drugs, and the surface area and pore volume of the MS. The findings of the study showed that the monomolecular loading capacity generally increased with increasing surface area and decreasing pore volume of the MS. However, the MS grade with the highest surface area did not display the highest monomolecular loading capacity for any of the three drugs. This was probably a result of the decreasing pore diameter necessary to accommodate the increasing surface area of the MS i.e., if the pore is smaller than the drug molecule, the drug cannot access the available surface area. For these systems, the amorphous density of the drug and the pore volume of the MS was used to estimate the theoretical pore filling capacity, which was in good agreement with the experimentally determined loading capacity. In conclusion, this study showed that both the pore volume and surface area of the MS will have an influence on the drug loading capacity and that this can be estimated with good accuracy both theoretically and experimentally., Competing Interests: None.

In this study, the performance of phase separated and crystallized amorphous solid dispersions (ASDs) was evaluated by non-sink in vitro dissolution testing in fasted-state simulated intestinal fluid (FaSSIF) and in vivo in rats. The amorphous phase-separated or crystallized ASDs were prepared by mixing an ASD of the model drug celecoxib (CCX) in polyvinylpyrrolidone (PVP) with pure amorphous or micronized crystalline CCX at 20, 40, 60 or 100% of the total drug load (25:75 w/w CCX:PVP), respectively. As expected, crystallization of CCX in the ASDs generally had a negative influence on both the area under the curve of the dissolution curve (in vitro AUC) and the plasma concentration-time profile (in vivo AUC) in rats compared to the pure ASD. However, the difference between the in vivo AUC of the pure ASD and the 20% and 40% crystallized ASDs was not statistically significant, which could indicate that a low fraction of crystallization of a drug in an ASD may only have limited impact on in vivo performance and hence bioavailability. In comparison, amorphous phase separation of CCX in the ASDs did not negatively influence the in vitro AUC and in vivo AUC to the same degree as crystallization and the dissolution profiles of all the amorphous phase-separated ASDs were similar to that of the pure ASD. In fact, even though a slight decrease of in vivo AUC with increasing fraction of amorphous phase separation was observed, the 20% and 40% amorphous phase-separated ASDs were bioequivalent with the pure ASD., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The aim of this study was to introduce a fast and reliable differential scanning calorimetry (DSC)-based method to determine the monomolecular loading capacity of drugs with good glass-forming ability in mesoporous silica (MS). The proposed method is based on a solvent-free melting/fusion of drug into the MS during a heat-cool-heat cycle in the DSC. Overloaded drug-MS systems were analyzed in the DSC at different drug ratios (50, 60, 70, 80 and 90% w/w) to quantify the excess drug in the (the fraction not adsorbed to the MS surface). During the first heating, the drug will melt and fuse into the pores of the MS and upon subsequent quench cooling, the drug that is not adsorbed to the surface of the MS will amorphize into a separate phase (as drugs with good glass-forming ability do not crystallize upon quench-cooling from the melt). The drug molecules adsorbed to the MS surface are "immobilized" and will not contribute to a glass transition in the DSC and thus, the excess drug can be quantified simply by determining the change in the heat capacity over the glass transition (ΔC p ). Since the ΔC p of overloaded samples decrease linearly with decreasing drug content, the monomolecular loading capacity of the drug in the MS can be determined by extrapolating to zero ΔC p . This value corresponds to the highest drug load at which the drug is monomolecularly adsorbed to the surface of the MS and has no drug-related thermal events (glass transition), i.e. a thermodynamically stable system. Using this method, it was possible to determine the monomolecular loading capacity of four drugs with good glass-forming ability in four different MS. These determinations were in good agreement with the physical stability of the systems during an accelerated stability study, which indicates that the thermoanalytical method enabled fast and reliable determination of the monomolecular loading capacity of drugs in MS., (Copyright © 2018 Elsevier B.V. All rights reserved.)

In this study, the influence of drug load on the microwave-induced amorphization of celecoxib (CCX) in polyvinylpyrrolidone (PVP) tablets was investigated using quantitative transmission Raman spectroscopy. A design of experiments (DoE) setup was applied for developing the quantitative model using two factors: drug load (10, 30, and 50% w/w) and amorphous fraction (0, 25, 50, 75 and 100%). The data was modeled using partial least-squares (PLS) regression and resulted in a robust model with a root mean-square error of prediction of 2.5%. The PLS model was used to study the amorphization kinetics of CCX-PVP tablets with different drug content (10, 20, 30, 40 and 50% w/w). For this purpose, transition Raman spectra were collected in 60 s intervals over a total microwave time of 10 min with an energy input of 1000 W. Using the quantitative model it was possible to measure the amorphous fraction of the tablets and follow the amorphization as a function of microwaving time. The relative amorphous fraction of CCX increased with increasing microwaving time and decreasing drug load, hence 90 ± 7% of the drug was amorphized in the tablets with 10% drug load whereas only 31 ± 7% of the drug was amorphized in the 50% CCX tablets. It is suggested that the degree of amorphization depends on drug loading. The likelihood of drug particles being in direct contact with the polymer PVP is a requirement for the dissolution of the drug into the polymer upon microwaving, and this is reduced with increasing drug load. This was further supported by polarized light microscopy that revealed evidence of crystalline particles and clusters in all the microwaved tablets., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The aim of the present study was to compare two DSC-based methods to predict drug-polymer solubility (melting point depression method and recrystallization method) and propose a guideline for selecting the most suitable method based on physicochemical properties of both the drug and the polymer. Using the two methods, the solubilities of celecoxib, indomethacin, carbamazepine, and ritonavir in polyvinylpyrrolidone, hydroxypropyl methylcellulose, and Soluplus® were determined at elevated temperatures and extrapolated to room temperature using the Flory-Huggins model. For the melting point depression method, it was observed that a well-defined drug melting point was required in order to predict drug-polymer solubility, since the method is based on the depression of the melting point as a function of polymer content. In contrast to previous findings, it was possible to measure melting point depression up to 20 °C below the glass transition temperature (T g ) of the polymer for some systems. Nevertheless, in general it was possible to obtain solubility measurements at lower temperatures using polymers with a low T g . Finally, for the recrystallization method it was found that the experimental composition dependence of the T g must be differentiable for compositions ranging from 50 to 90% drug (w/w) so that one T g corresponds to only one composition. Based on these findings, a guideline for selecting the most suitable thermal method to predict drug-polymer solubility based on the physicochemical properties of the drug and polymer is suggested in the form of a decision tree., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The present study investigated the influence of in vitro dissolution conditions on the in vivo predictability of an amorphous solid dispersion of celecoxib (CCX) in the pH-sensitive polymer Eudragit ® S 100. Different doses of a 25:75w/w% CCX:Eudragit ® S 100 amorphous solid dispersion (CCX:EUD) were investigated. During in vitro dissolution a significant effect of the pH of the dissolution media on the release of CCX was observed. In fasted state simulated intestinal fluid (FaSSIF) pH 6.5, the release of CCX from the amorphous solid dispersion was comparable to that of crystalline CCX and lower than that of amorphous CCX whereas in FaSSIF pH 7.4, the release was significantly increased compared to both crystalline and amorphous CCX. With a 3-fold increase in the exposure of CCX:EUD compared to crystaline CCX. The in vivo data also suggested that Eudragit ® S 100 was suitable as a carrier in amorphous solid dispersions of CCX. In vitro-in vivo correlation demonstrated that the in vitro data obtained in FaSSIF pH 7.4 was more predictive for the in vivo performance than that obtained in FaSSIF pH 6.5. Consequently, the findings of this study underline that when predicting the in vivo performance of amorphous solid dispersions with pH-sensitive polymers, it is imperative that the in vitro dissolution conditions are carefully considered., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The established methods to predict drug-polymer solubility at room temperature either rely on extrapolation over a long temperature range or are limited by the availability of a liquid analogue of the polymer. To overcome these issues, this work investigated a new methodology where the drug-polymer solubility is estimated from the solubility of the drug in a solution of the polymer at room temperature using the shake-flask method. Thus, the new polymer in solution method does not rely on temperature extrapolations and only requires the polymer and a solvent, in which the polymer is soluble, that does not affect the molecular structure of the drug and polymer relative to that in the solid state. Consequently, as this method has the potential to provide fast and precise estimates of drug-polymer solubility at room temperature, we encourage the scientific community to further investigate this principle both fundamentally and practically., (Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

This study investigated the non-sink in vitro dissolution behavior and in vivo performance in rats of celecoxib (CCX) amorphous solid dispersions with polyvinyl acetate (PVA), polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose (HPMC) at different drug doses. Both in vitro and in vivo, the amorphous solid dispersions with the hydrophilic polymers PVP and HPMC led to higher areas under both, the in vitro dissolution and the plasma concentration-time curves (AUC) compared to crystalline and amorphous CCX for all doses. In contrast, the amorphous solid dispersion with the hydrophobic polymer PVA showed a lower AUC both in vitro and in vivo than crystalline CCX. For crystalline CCX and CCX:PVA, the in vitro AUC was limited by the low solubility of the drug and the slow release of the drug from the hydrophobic polymer, respectively. For the supersaturating formulations, amorphous CCX, CCX:PVP and CCX:HPMC, the in vitro performance was mainly dependent on the dissolution rate and precipitation/crystallization inhibition of the polymer. As expected, the crystallization tendency increased with increasing dose, and therefore the in vitro AUCs did not increase proportionally with dose. Even though the in vivo AUC for all formulations increased with increasing dose, the relative bioavailability decreased significantly, indicating that the supersaturating formulations also crystallized in vivo and that the absorption of CCX was solubility-limited. These findings underline the importance of evaluating relevant in vitro doses, in order to rationally assess the performance of amorphous solid dispersions and avoid confusion in early in vivo studies., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Differential scanning calorimetry (DSC) is frequently the thermal analysis technique of choice within preformulation and formulation sciences because of its ability to provide detailed information about both the physical and energetic properties of a substance and/or formulation. However, conventional DSC has shortcomings with respect to weak transitions and overlapping events, which could be solved by the use of the more sophisticated modulated DSC (mDSC). mDSC has multiple potential applications within the pharmaceutical field and the present review provides an up-to-date overview of these applications. It is aimed to serve as a broad introduction to newcomers, and also as a valuable reference for those already practising in the field. Complex mDSC was introduced more than two decades ago and has been an important tool for the quantification of amorphous materials and development of freeze-dried formulations. However, as discussed in the present review, a number of other potential applications could also be relevant for the pharmaceutical scientist., (Copyright © 2015 Elsevier B.V. All rights reserved.)

In this study, the influence of the molecular weight of polyvinylpyrrolidone (PVP) on the non-sink in vitro dissolution and in vivo performance of celecoxib (CCX):PVP amorphous solid dispersions were investigated. The dissolution rate of CCX from the amorphous solid dispersions increased with decreasing PVP molecular weight and crystallization inhibition was increased with increasing molecular weight of PVP, but reached a maximum for PVP K30. This suggested that the crystallization inhibition was not proportional with molecular weight of the polymer, but rather there was an optimal molecular weight where the crystallization inhibition was strongest. Consistent with the findings from the non-sink in vitro dissolution tests, the amorphous solid dispersions with the highest molecular weight PVPs (K30 and K60) resulted in significantly higher in vivo bioavailability (AUC0-24h) compared with pure amorphous and crystalline CCX. A linear relationship between the in vitro and in vivo parameter AUC0-24h indicated that the simple non-sink in vitro dissolution method used in this study could be used to predict the in vivo performance of amorphous solid dispersion with good precision, which enabled a ranking between the different formulations. In conclusion, the findings of this study demonstrated that the in vitro and in vivo performance of CCX:PVP amorphous solid dispersions were significantly controlled by the molecular weight of the polymer., (Copyright © 2016 Elsevier B.V. All rights reserved.)

In this study, the influence of copolymer composition on drug-polymer solubility was investigated. The solubility of the model drug celecoxib (CCX) in various polyvinylpyrrolidone/vinyl acetate (PVP/VA) copolymer compositions (70/30, 60/40, 50/50 and 30/70 w/w) and the pure homopolymers polyvinylpyrrolidone (PVP) and polyvinyl acetate (PVA) was predicted at 25 °C using a thermal analysis method based on the recrystallization of a supersaturated amorphous dispersion (recrystallization method). These solubilities were compared with a prediction based on the solubility of CCX in the liquid monomeric precursors of PVP/VA, N-vinylpyrrolidone (NVP) and vinyl acetate (VA), using the Flory-Huggins lattice theory (liquid monomer solubility approach). The solubilities predicted from the liquid monomer solubility approach increased linearly with increasing VP/VA ratio from 0.03-0.60 w/w. Even though the solubilities predicted from the recrystallization method also increased with increasing VP/VA ratio from 0.02-0.40 w/w, the predicted solubility seemed to approach a plateau at high VP/VA ratios. Increasing positive deviations from the Gordon-Taylor equation with increasing VP/VA ratio indicated strong interactions between CCX and the VP repeat unit, which was in accordance with the relatively high solubilities predicted using both methods. As the solubility plateau may be a consequence of steric hindrance caused by the size differences between CCX and the VP repeat units, it is likely that a CCX molecule interacting with a VP repeat unit hinders another CCX molecule from binding to the neighboring repeat units in the polymer chain. Therefore, it is possible that replacing these neighboring hygroscopic VP repeat units with hydrophobic VA repeat units, could increase the physical stability of an amorphous solid dispersion without compromising the drug-polymer solubility. This knowledge could be used advantageously in future development of amorphous drug delivery systems as copolymers could be customized to provide optimal drug-polymer solubility and physical stability., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Previous studies suggested that an amorphous solid dispersion with a copolymer consisting of both hydrophobic and hydrophilic monomers could improve the dissolution profile of a poorly water-soluble drug compared to the crystalline form. Therefore, this study investigated the influence of the copolymer composition of polyvinylpyrrolidone/vinyl acetate (PVP/VA) on the non-sink in vitro dissolution behavior and in vivo performance of celecoxib (CCX) amorphous solid dispersions. The study showed that the hydrophilic monomer vinylpyrrolidone (VP) was responsible for the generation of CCX supersaturation whereas the hydrophobic monomer vinyl acetate (VA) was responsible for the stabilization of the supersaturated solution. For CCX, there was an optimal copolymer composition around 50-60% VP content where further replacement of VP monomers with VA monomers did not have any biopharmaceutical advantages. A linear relationship was found between the in vitro AUC(0-4h) and in vivo AUC(0-24h) for the CCX:PVP/VA systems, indicating that the non-sink in vitro dissolution method applied in this study was useful in predicting the in vivo performance. These results indicated that when formulating a poorly water-soluble drug as an amorphous solid dispersion using a copolymer, the copolymer composition has a significant influence on the dissolution profile and in vivo performance. Thus, the dissolution profile of a drug can theoretically be tailored by changing the monomer ratio of a copolymer with respect to the required in vivo plasma-concentration profile. As this ratio is likely to be drug dependent, determining the optimal ratio between the hydrophilic (dissolution enhancing) and hydrophobic (crystallization inhibiting) monomers for a given drug is imperative.

In this study, a method proposed to predict drug-polymer miscibility from differential scanning calorimetry measurements was subjected to statistical analysis. The method is relatively fast and inexpensive and has gained popularity as a result of the increasing interest in the formulation of drugs as amorphous solid dispersions. However, it does not include a standard statistical assessment of the experimental uncertainty by means of a confidence interval. In addition, it applies a routine mathematical operation known as "transformation to linearity," which previously has been shown to be subject to a substantial bias. The statistical analysis performed in this present study revealed that the mathematical procedure associated with the method is not only biased, but also too uncertain to predict drug-polymer miscibility at room temperature. Consequently, the statistical inference based on the mathematical procedure is problematic and may foster uncritical and misguiding interpretations. From a statistical perspective, the drug-polymer miscibility prediction should instead be examined by deriving an objective function, which results in the unbiased, minimum variance properties of the least-square estimator as provided in this study.

In this study, a comparison of different methods to predict drug-polymer solubility was carried out on binary systems consisting of five model drugs (paracetamol, chloramphenicol, celecoxib, indomethacin, and felodipine) and polyvinylpyrrolidone/vinyl acetate copolymers (PVP/VA) of different monomer weight ratios. The drug-polymer solubility at 25 °C was predicted using the Flory-Huggins model, from data obtained at elevated temperature using thermal analysis methods based on the recrystallization of a supersaturated amorphous solid dispersion and two variations of the melting point depression method. These predictions were compared with the solubility in the low molecular weight liquid analogues of the PVP/VA copolymer (N-vinylpyrrolidone and vinyl acetate). The predicted solubilities at 25 °C varied considerably depending on the method used. However, the three thermal analysis methods ranked the predicted solubilities in the same order, except for the felodipine-PVP system. Furthermore, the magnitude of the predicted solubilities from the recrystallization method and melting point depression method correlated well with the estimates based on the solubility in the liquid analogues, which suggests that this method can be used as an initial screening tool if a liquid analogue is available. The learnings of this important comparative study provided general guidance for the selection of the most suitable method(s) for the screening of drug-polymer solubility.

In this study, the influence of polymer molecular weight on drug-polymer solubility was investigated using binary systems containing indomethacin (IMC) and polyvinylpyrrolidone (PVP) of different molecular weights. The experimental solubility in PVP, measured using a differential scanning calorimetry annealing method, was compared with the solubility calculated from the solubility of the drug in the liquid analogue N-vinylpyrrolidone (NVP). The experimental solubility of IMC in the low-molecular-weight PVP K12 was not significantly different from that in the higher molecular weight PVPs (K25, K30, and K90). The calculated solubilities derived from the solubility in NVP (0.31-0.32 g/g) were found to be lower than those experimentally determined in PVP (0.38-0.40 g/g). Nevertheless, the similarity between the values indicates that the analogue solubility can provide valuable indications on the solubility in the polymer. Hence, if a drug is soluble in an analogue of the polymer, it is most likely also soluble in the polymer. In conclusion, the solubility of a given drug-polymer system is determined by the strength of the drug-polymer interactions rather than the molecular weight of the polymer. Therefore, during the first screenings for drug solubility in polymers, only one representative molecular weight per polymer is needed., (© 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.)

In this study, the influence of the preparation technique (ball milling, spray drying, and film casting) of a supersaturated amorphous dispersion on the quality of solubility determinations of indomethacin in polyvinylpyrrolidone was investigated by means of statistical analysis. After annealing of the amorphous dispersions above the crystallization temperature for 2 h, the solubility curve was derived from the glass transition temperature of the demixed material using the Gordon-Taylor relationship and fitting with the Flory-Huggins model. The study showed that the predicted solubility from the ball-milled mixtures was not consistent with those from spray drying and film casting, indicating fundamental differences between the preparation techniques. Through formal statistical analysis, the best combination of fit to the Flory-Huggins model and reproducibility of the measurements was analyzed. Ball milling provided the best reproducibility of the three preparation techniques; however, an analysis of residuals revealed a systematic error. In contrast, film casting demonstrated a good fit to the model but poor reproducibility of the measurements. Therefore, this study recommends that techniques such as spray drying or potentially film casting (if experimental reproducibility can be improved) should be used to prepare the amorphous dispersions when performing solubility measurements of this kind., (© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.)

Precipitation of cinnarizine during in vitro lipolysis of a self-microemulsifying drug delivery system (SMEDDS) was characterized to gain a better understanding of the mechanisms behind the precipitation. During in vitro lipolysis of the SMEDDS with or without cinnarizine, samples were taken at several timepoints and ultracentrifuged. Cinnarizine content in the pellet increased from 4% to 59% during lipolysis. The precipitation of cinnarizine during in vitro lipolysis correlated well with the degree of lipid digestion, determined by sodium hydroxide addition. The pellet from the endpoint of lipolysis was isolated and subjected to dissolution in biorelevant media. Dissolution rate of cinnarizine from pellets containing precipitated cinnarizine was initially 10-fold higher than dissolution from blank pellet spiked with crystalline cinnarizine, reaching more than 50% drug dissolved in the first minute. Pellets were further characterized by X-ray powder diffraction (XRPD) and polarized light microscopy (PLM). Both methods indicated the presence of liquid crystalline phases of calcium fatty acid soaps, but no presence of crystalline cinnarizine in the pellet. Overall, dissolution studies along with XRPD and PLM analysis indicate that cinnarizine precipitating during in vitro lipolysis of this SMEDDS is not crystalline, suggesting an either amorphous form or a molecular dispersion., (© 2010 Wiley-Liss, Inc. and the American Pharmacists Association)