TY - JOUR

T1 - Microwave induced in situ amorphisation facilitated by crystalline hydrates

AU - Holm, Tobias Palle

AU - Knopp, Matthias Manne

AU - Löbmann, Korbinian

AU - Berthelsen, Ragna

N1 - Publisher Copyright: © 2021 Elsevier B.V.

PY - 2021

Y1 - 2021

N2 - 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 (NaH2PO4) di-, and monohydrate, in compacts prepared with 30 % w/w celecoxib (CCX) in polyvinylpyrrolidone K12 (PVP). As controls, compacts prepared with NaH2PO4 anhydrate and without NaH2PO4 were included in the study. The quantification of amorphous CCX after microwave irradiation showed an increase in CCX amorphicity for compacts containing NaH2PO4 di-, and monohydrate with increasing irradiation time. Complete amorphisation of CCX in compacts containing NaH2PO4 di-, and monohydrate was observed after 6 min, while no appreciable amorphisation was observed for the control compacts containing NaH2PO4 anhydrate and without NaH2PO4. Modulated differential scanning calorimetric analysis revealed that a homogenous ASD was formed after 12 min and 6 min for compacts containing NaH2PO4 di-, and monohydrate, respectively. Thermal gravimetric analysis indicated that NaH2PO4 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 NaH2PO4 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.

AB - 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 (NaH2PO4) di-, and monohydrate, in compacts prepared with 30 % w/w celecoxib (CCX) in polyvinylpyrrolidone K12 (PVP). As controls, compacts prepared with NaH2PO4 anhydrate and without NaH2PO4 were included in the study. The quantification of amorphous CCX after microwave irradiation showed an increase in CCX amorphicity for compacts containing NaH2PO4 di-, and monohydrate with increasing irradiation time. Complete amorphisation of CCX in compacts containing NaH2PO4 di-, and monohydrate was observed after 6 min, while no appreciable amorphisation was observed for the control compacts containing NaH2PO4 anhydrate and without NaH2PO4. Modulated differential scanning calorimetric analysis revealed that a homogenous ASD was formed after 12 min and 6 min for compacts containing NaH2PO4 di-, and monohydrate, respectively. Thermal gravimetric analysis indicated that NaH2PO4 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 NaH2PO4 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.

KW - Amorphous solid dispersion

KW - Celecoxib

KW - Hydrates

KW - In situ amorphisation

KW - Microwave radiation

KW - Polyvinylpyrrolidone

KW - Sodium dihydrogen phosphate

U2 - 10.1016/j.ejps.2021.105858

DO - 10.1016/j.ejps.2021.105858

M3 - Journal article

C2 - 33887432

AN - SCOPUS:85105328887

VL - 163

JO - Norvegica Pharmaceutica Acta

JF - Norvegica Pharmaceutica Acta

SN - 0928-0987

M1 - 105858

ER -