Process parameters of microsphere preparation based on propylene carbonate emulsion-precursors.

AIM: This study aimed for a detailed understanding of the impact of different process parameters involved during celecoxib-loaded microsphere preparation based on propylene carbonate emulsion-precursors. METHODS: Microspheres were prepared by a modified emulsification-solvent extraction method. Performed investigations included polymer solubility and viscosity, microsphere size, morphology and stability, propylene carbonate content as well as celecoxib solid state, content and release. RESULTS: Rough-walled round microspheres with sizes between 21 µm and 122 µm and an internal sponge-like structure filled with residual propylene carbonate (content between 1.9 ± 0.1% and 6.7 ± 0.5% w/w) were obtained. Encapsulation efficiencies varied between 28.3 ± 0.1% and 66.8 ± 1.0%. The release rates were affected by the polymer concentration, the emulsion phase ratio and the residual propylene carbonate content (t50% varied between 2.2 hours and 23.4 hours). CONCLUSIONS: This study identified the most relevant process parameters for this new preparation method for the model drug celecoxib.

Predictability of drug encapsulation and release from propylene carbonate/PLGA microparticles.

Key parameters for microparticle-based parenteral depot formulation development are entrapment efficiency and sustained drug release, which both depend on the intermolecular affinity of the components. Here, partial solubility parameters were evaluated as descriptors for 21 drug substances and 3 polymers in propylene carbonate (PC). Out of these 21 drug substances, eight BCS class II substances (celecoxib, clotrimazole, erythromycin, ibuprofen, indomethacin, itraconazole, lopinavir and ritonavir) were encapsulated using PLGA (Poly(DL-lactide-co-glycolide)) as polymer matrix and PC as a polar aprotic solvent in order to assign microparticle properties to potential affinity-related interactions using partial solubility parameters. Microparticle morphology was highly dependant on the specific glass transition temperature (Tg) of the encapsulated drug substance. A strong correlation (R = 0.912) between the encapsulation efficiency and the difference in total solubility parameter (Δδt API-PLGA) underlined the encapsulation predictability. Moreover, in drug release, a significant impact of Δδt API-PLGA on initial burst was observed and even more pronounced on the release rate of the encapsulated drug substance. The possibility to predict these important microparticle properties underline the value of including solubility descriptors such as partial solubility parameters into microparticle formulation development.

Microparticle preparation by a propylene carbonate emulsification-extraction method.

The use of various harmful organic solvents for microparticle formulations is still widespread. Here, an alternative low toxicity solvent (propylene carbonate; PC) is proposed for the preparation of poly(lactic-co-glycolic-acid) (PLGA) microparticles. Based on the classical emulsification-solvent extraction methodology, the use of PC offers the unique advantage of an additional solvent extraction step using hydrolytic solvent cleavage during microparticle preparation. Spherical, rough-surfaced microparticles were obtained with a volume median diameter range from 20 to 60 µm. The residual PC content has been identified to be the major factor for the solidification hindrance, leading to polymeric Tg shifting due to a plasticizing effect. When applying the enhanced PC extraction step, the residual PC content was lowered from 8.8% to 2.7% and subsequently Tg values shifted from 8.2 to 37.7 °C. Additionally, the hydrolytic solvent cleavage confirmed to have no impact on the PLGA stability. This method presents a significant advancement towards replacing of conventional solvents in the microparticle preparation due to more efficient solvent extraction.

Propylene carbonate quantification by its derivative 3,5-diacetyl-1,4-dihydro-2,6-lutidine.

Propylene carbonate (PC) is a non-toxic solvent currently used in various pharmaceutical formulations. Consequently, a simple, cost-effective and most accurate analytical method for the quantification of this optical inert solvent is of major interest. Based on a consecutive three-step reaction 3,5-diacetyl-1,4-dihydro-2,6-lutidine was obtained from PC and used for quantification by either UV and fluorescent detection. Data were compared with results from LC-ESI-MS as a reference method. After using Mandel's test for linearity assessment of the calibration curves, linear fitting was used for LC-ESI-MS and spectrofluorimetry, while a polynomial 3rd order curve fitting was used for spectrophotometry. High intra- and inter-day precision as well as high accuracy were confirmed for all three analytical methods (spectrophotometry, spectrofluorimetry and LC-ESI-MS). The comparison of all three methods was assessed using correlation coefficients and Bland-Altman plots, both showing satisfying results with a high degree of agreement. The new method confirmed its applicability for PC quantification in two formulations, namely a PC-enriched cream and polyester microimplants. This new quantification method for PC is a reliable alternative to highly sophisticated chromatographic methods.