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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 (Tg) 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 (Mw) 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 Mw of polyvinylpyrrolidone (PVP: PVP12, PVP17 or PVP25), 0.25 wt% plasmonic nanoaggregates (PNs) and 0.5 wt% lubricant, the effect of the polymer Mw 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 Mw (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. [ABSTRACT FROM AUTHOR]

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 (Tg) 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 Tg, 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., TDStart. 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 TDStart. [ABSTRACT FROM AUTHOR]

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 (Tg) of the polymer. Thus, increasing the compact temperature, above the Tg 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 Tg 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. [ABSTRACT FROM AUTHOR]

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 (Tg) 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 Tg, 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 Tg, is further strengthened. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. Microwave-induced in situ amorphization was achieved using compact containing a physical mixture of the model drug celecoxib and the polymers, polyethylene glycol and polyvinylpyrrolidone. [Display omitted] [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [Display omitted] [ABSTRACT FROM AUTHOR]