Browsing by Subject "indometasiini"

Solid materials can exist in two major forms: in crystalline or amorphous form. Amorphous form is defined as no long term order existing in solid structure in molecular scale. Amorphous materials have different physicochemical properties compared crystalline forms of same substance. Amorphous materials doesn't have sharp melting point as crystalline materials. When heated above so called glass transition temperature amorphous materials become rubbery (plasticization) and when cooled below they become glassy (hard and brittle). Amorphous forms can also have different dissolution properties which makes them useful in formulation of poorly soluble drugs. Amorphous forms are less stable compared to crystalline form. That's due amount of free energy stored in it's structures. Amorphous materials can be manufactured in many ways including quench cooling, hot-melt-extrusion, spray drying and lyophilisation (freeze drying). In experimental section effect of grinding method in properties of amorphous indomethacin was studied. Amorphous indomethacin was prepared by quenching of melt in liquid nitrogen. Properties of amorphous indomethacin was studied by x-ray powder diffraction and differential scanning calorimetry. Measurements were performed in different time stamps varied form 0 to 92 days. Measured properties were crystalline content, glass transition temperature, change in heath capacity, heat of crystallization, heat of melting and melting points of crystallized forms. Calorimetry data was recorded only from totally amorphous samples. It can be seen in results that different patches are not comparable statistically but when comparing room temperature ground and liquid nitrogen ground samples to each other differences can be found in every set. Difference is observed in initial time of crystallization (time when crystallinity can be measured first time) and in thermodynamical properties such as change in heat capacity, glass transition temperature and heat of melting. Solid dispersions of indomethacin and xylitol were prepared in 3 different compositions (5%, 10% and 20% xylitol in indomethacin). XRPD and DSC data were measured at different time stamps (aged 1 to 63 days). 5% and 10% dispersions found to be stabile and being amorphous in all time stamps. 20% dispersion was already partly crystallized at 63 days (especially liquid nitrogen ground sample).

Pharmaceutical nanocrystals are under one micrometer sized crystals composed of pure active pharmaceutical ingredient (API) and stabilizer. Their apparent dissolution rate is improved compared to conventionally sized crystals. Rapid dissolution is mainly due to increased intrinsic surface area of API powder. Solubility increase is significant only with very small, under 100 nm crystals. Nanocrystal formulations with improved dissolution rates can be utilized to increase bioavailability of fairly insoluble BCS class II APIs. Few nanocrystal based products are already on market. Common methods for dissolution study of nanocrystals arecompendial dissolution apparatus 1 or 2, which usually rely on sampling and separation of undissolved fraction. The reliability of these methods is dependent of the separation efficiency. Unfortunately separation becomes more tedious with diminishing crystal size. Thus it would be desirable to replace the methods that require sampling and separation with methods that do not require separation of undissolved fraction (in situ methods), preferably with continuous detection. With the dialysis method the separation is easily achieved. However, the rate limiting step is not dissolution but diffusion through the dialysis membrane. Electrochemical in situ detection methods can only be applied to electroactive APIs. Utilization of in situ UV probes for monitoring nanocrystal dissolution is limited by the UV absorbance of the nanocrystals themselves. To date, light scattering methods have mainly been applied to solubility studies, with few attempts on dissolution studies. In this study the light scattering, dialysis and compendial paddle methods were compared for their ability to monitor the dissolution of indometacin nanosuspensions (NS). Light scattering experiments were performed with Zetasizer equipment. Three poloxamer 188 stabilized NSs, with average diameters (Dz) of 300 nm, 600 nm, and 900 nm, were evaluated. Dissolution studies were executed in sink conditions (under 30% of saturated concentration) and in slightly higher concentration (intermediate conc., 30-50% of saturated concentration) at pH 5.5. The compendial paddle method was performed on the same suspensions with the same medium at intermediate concentration. In the dialysis method the studied NS had a Dz value of 350 nm. The pH of the dissolution medium was 7.4, and the membrane was made of regenerated cellulose. Experimental results were fitted to exponential equation and the dissolution time DT, i.e. time to reach 99% dissolution, was determined based on the equation. In sink conditions the dissolution of all of the NSs was so rapid that reliable estimations of dissolution times could not be made with the light scattering method. In intermediate concentration the dissolution time (51±12 s) of the 300 nm NS was significantly lower than those of 600 nm (340±80 s) and 900 nm (230±50 s) NSs with a confidence level of 5%. The slowest dissolution of the 600 nm NS could be attributed to its broad crystal size distribution. With the compendial paddle method no significant differences in dissolution times could be detected. Compendial dissolution times, about 600-700 s, were markedly longer than those from light scattering experiments. The dialysis method was unable to discriminate between 350 nm NS and indometacin solution, which can be explained by rapid dissolution of the nanocrystals, followed by slow diffusion across the dialysis membrane. Of the studied methods, light scattering was the only one to discriminate between dissolution times of various NSs. It was most applicable to narrow crystal size distributions. It is a fairly small scale method requiring only 1 mL of dissolution medium and about 10 µg of nanocrystals. The method was not dependent on chemical analysis. Theost important limitation was the fact that due to the operational method of the Zetasizer, the first data point was not acquired until about 20 s after the measurement started.