Effect of Drug Loading in Mesoporous Silica on Amorphous Stability and Performance.

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 Cmax, Tmax and dissolution rate.

The interplay between trehalose and dextran as spray drying precursors for cationic liposomes.

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.

Studying the Impact of the Temperature and Sorbed Water during Microwave-Induced In Situ Amorphization: A Case Study of Celecoxib and Polyvinylpyrrolidone.

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.

Microwave-Induced in Situ Drug Amorphization Using a Mixture of Polyethylene Glycol and Polyvinylpyrrolidone.

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.

Convection-Induced vs. Microwave Radiation-Induced in situ Drug Amorphization.

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.

The influence of drug and polymer particle size on the in situ amorphization using microwave irradiation.

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 (Tg) 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 Tg of the compacts. Hence, prolonging the exposure time above the Tg, 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.

The Influence of Temperature and Viscosity of Polyethylene Glycol on the Rate of Microwave-Induced In Situ Amorphization of Celecoxib.

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.

The role interplay between mesoporous silica pore volume and surface area and their effect on drug loading capacity.

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.

Precipitation of a poorly soluble model drug during in vitro lipolysis: characterization and dissolution of the precipitate.

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.