Browsing by Subject "indomethacin"

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).

The majority of potential new chemical entities reaching drug development phase belong to Class II the Biopharmaceutics Classification System (BCS) which complicates formulation of orally administered drugs. Therefore, there is a need to develop methods to increase the solubility and dissolution rate. Transformation of a crystalline drug into its amorphous form can be used to enhance these properties of poorly water-soluble drugs. However, amorphous drugs are thermodynamically unstable and tend to recrystallize back to the crystalline form. Coamorphous forms are a new and promising method to stabilize amorphous form. A relatively new approach is to combine the active drug compound with an amino acid to form a coamorphous system. In this study, co-amorphous systems were prepared from gamma, alpha or amorphous form of indomethacin (IND) and tryptophan (TRP) by ball milling. The solid-state changes during milling were investigated to obtain information about the co-amorphization process. The main objective was to investigate the effects of initial solid state of indomethacin on the formation pathways. In addition, different analytical methods were compared with respect to observed endpoints of the formation process. Raman spectroscopy has not been used in previous studies regarding solid state changes in co-amorphous forms. The presence of fluorescence in amorphous systems may have limited use of the method. A time-gated Raman setup together with X-ray powder diffraction and differential scanning calorimetry (DSC) was used to investigate this kind of potentially fluorescent system. Principal component analysis of spectral data revealed that the three different binary systems had individual and direct pathways towards the same end points during milling. This indicates that the co-amorphous form formed after 60 minutes of ball milling is not dependent on the initial solid-state form of IND. Straight pathways also indicated direct transformation to the coamorphous form. DSC was found to be the most sensitive method to detect changes for the longest period during co-amorphization. Conventional Raman spectroscopy was found to be suitable for investigation of the co-amorphization process. However, time-gated Raman spectroscopy did not show significant advantages compared to conventional Raman data. This study revealed that the most stable form of IND could be used for production of co-amorphous form together with TRP. Raman spectroscopy could potentially be used for investigating coamorphization also as an in-process analytical method.

Improvements in drug screening technology have resulted in a situation where more poorly soluble compounds enter the drug development pipeline. Poor aqueous solubility is a major issue especially in preclinical toxicity testing, where the generation of high drug loads is needed. For oral delivery, liquid formulations are often used and suspensions are potential options for poorly soluble drugs. While several different techniques to enhance solubility exist, most of them have method specific disadvantages or are not universal. Solid state modification, and especially the use of the high energy amorphous form, offers an efficient technique to enhance dissolution properties of a wide range of compounds. A problem of the amorphous form, however, is its physical instability. Amorphous drug in aqueous suspension can re-crystallize via solid-solid and/or solution-mediated pathways. To maintain the solubility advantage of amorphous forms for sufficient period of time, stabilization is needed. One way to stabilize the amorphous form is to prepare a solid dispersion, where the amorphous drug is dispersed in a stabilizing hydrophilic carrier matrix. Another way to add stabilizing agents is to dissolve them into the suspension medium prior to the amorphous solids. Solubilizing polymers may elevate the equilibrium solubility and reduce the driving force for solution mediated crystallization. The aims of this study were to stabilize amorphous indomethacin in aqueous suspensions and to understand the mechanisms behind stabilization. Indomethacin (IND) was used as a poorly soluble model drug (BCS class II). Four different polymers (PVP, HPMC, HPMC-AS and Soluplus®) were selected as stabilizing agents. Crystallization of solid amorphous IND and the concentration of dissolved IND in water were studied after adding: i) the pure amorphous IND, ii) solid dispersions (SDs) at 1:1 and 9:1 drug:polymer ratios (w/w), and iii) the pure amorphous IND into aqueous medium containing predissolved polymer at concentrations of 10 mg/ml or 1 mg/ml, total drug and polymer concentrations being equivalent to 1:1 and 9:1 drug:polymer ratios (w/w) in the SDs, respectively. For HPMC-AS only a 1 mg/ml polymer concentration was used due to its limited solubility. Both the solid and solution phases of the suspension were analysed at different time points for up to 24 h or until crystallization had occurred. Phase transformations in the solid phase were analysed using ATR-FT-IR spectroscopy combined with principal component analysis. The concentration of dissolved drug over the time was assessed by UV spectroscopy. In general, all the polymers, either in SDs or pre-dissolved in medium delayed the onset of crystallization of amorphous IND. Higher polymer concentrations inhibited the crystallization longer than lower ones. A general trend was that SDs were superior in stabilization of amorphous solids, but pre-dissolved polymer solutions generated and maintained higher IND concentrations in solution. Of the four polymers studied, Soluplus® showed the most promising results: SD of Soluplus® and IND at 1:1 ratio (w/w) stayed amorphous in aqueous medium for more than 28 days. On the other hand, crystallization was quite rapid (30 min) when the amount of polymer was inadequate (9:1 w/w). Soluplus® solution (10 mg/ml) generated a 20-fold higher IND concentration than the corresponding SD, possibly due to micellisation. Different polymers showed different abilities to inhibit crystallization and enhance the drug concentration in solution. The addition method and the drug-polymer ratio had an influence on the stabilization abilities of the polymer. Stabilization mechanisms may be both thermodynamic (type of polymer) and kinetic(method of addition).