Impact of alternative solid state forms and specific surface area of high-dose, hydrophilic active pharmaceutical ingredients on tabletability

YesIn order to investigate the effect of using different solid state forms and specific surface area (TBET) of active pharmaceutical ingredients on tabletability and dissolution performance, the mono- and dihydrated crystalline forms of chlorothiazide sodium and chlorothiazide potassium (CTZK) salts were compared to alternative anhydrous and amorphous forms, as well as to amorphous microparticles of chlorothiazide sodium and potassium which were produced by spray drying and had a large specific surface area. The tablet hardness and tensile strength, porosity, and specific surface area of single-component, convex tablets prepared at different compression pressures were characterized. Results confirmed the complexity of the compressibility mechanisms. In general it may be concluded that factors such as solid-state form (crystalline vs amorphous), type of hydration (presence of interstitial molecules of water, dehydrates), or specific surface area of the material have a direct impact on the tabletability of the powder. It was observed that, for powders of the same solid state form, those with a larger specific surface area compacted well, and better than powders of a lower surface area, even at relatively low compression pressures. Compacts prepared at lower compression pressures from high surface area porous microparticles presented the shortest times to dissolve, when compared with compacts made of equivalent materials, which had to be compressed at higher compression pressures in order to obtain satisfactory compacts. Therefore, materials composed of nanoparticulate microparticles (NPMPs) may be considered as suitable for direct compaction and possibly for inclusion in tablet formulations as bulking agents, APIs, carriers, or binders due to their good compactibility performanceSolid State Pharmaceutical Cluster (SSPC), supported by Science Foundation Ireland under Grant No. 07/SRC/B1158

Co-crystallization of sucrose at high concentration in the presence of glucose and fructose

Co-crystallization of sucrose from a highly concentrated sucrose syrup (less than or equal to 7% moisture, w/w) at 131 degreesC with 0, 5, 10, 15, and 20% of fructose, glucose, or a mixture of fructose and glucose was investigated. The crystallization of sucrose was delayed in presence of these lower molecular weight sugars. The DSC melting endotherm of cocrystallized samples exhibited a decrease in crystalline sucrose in the sample as a function of increased level of glucose and fructose. The mechanical strength of co-crystallized granules was found to be related to the moisture content and the amount of glucose or fructose content in the sample. The samples containing 10, 15, and 20% glucose in co-crystallized product demonstrated crystallization of glucose in its monohydrate form during 1 mo of storage

Studies of the Crystallization of Amorphous Trehalose Using Simultaneous Gravimetric Vapor Sorption/Near IR (GVS/NIR) and “Modulated” GVS/NIR

The purpose of this research was to investigate the influence of changes in the amorphous state on the crystallization of trehalose. Amorphous trehalose is known to stabilize biomaterials; hence, an understanding of crystallization is vital. Amorphous trehalose, prepared by spray-drying, was exposed to either a single step (0–75%) in relative humidity (RH) or to modulated 0–75–0% RH to cause crystallization. For the single-step experiment, two samples crystallized in a predictable manner to form the dihydrate. One sample, while notionally identical, did not crystallize in the same way and showed a mass loss throughout the time at 75% RH, with a final mass less than that expected for the dihydrate. The idiosyncratic sample was seen to have a starting near infrared (NIR) spectra similar to that exhibited by anhydrous crystalline trehalose, implying that short-range order in the amorphous material (or a small amount of crystalline seed, not detectable using powder X-ray diffraction) caused the sample to fail to form the dihydrate fully when exposed to high RH. The modulated RH study showed that the amorphous material interacted strongly with water; the intensity of the NIR traces was not proportional to mass of water but rather the extent of hydrogen bonding. Subsequent crystallization of this sample clearly was a partial formation of the dihydrate, but with the bulk of the sample then shielded such that it was unable to show significant sorption when exposed to elevated RH. It has been shown that the nature of the amorphous form will alter the way in which samples crystallize. With oscillation in RH, it was possible to further understand the interactions between water and amorphous trehalose

Effects of water vapor absorption on the physical and chemical stability of amorphous sodium indomethacin

This study reports on the effects that water absorbed into amorphous sodium indomethacin (NaIMC) can have on simultaneous tendencies to crystallize to its trihydrate form and to undergo base-catalyzed hydrolysis because of the plasticizing effects of water on molecular mobility. Measurement of water vapor absorption at 30°C and powder x-ray diffraction patterns as a function of relative humidity (RH) reveal that upon exposure to 21% RH, NaIMC does not crystallize over a 2-month period. Measurements of the glass transition temperature as a function of such exposure reveals a change in Tg from 121°C, dry, to 53°C at 21% RH, such that Tg at 21% RH is ≈13°C above the highest storage temperature of 40°C used in the study. At 56% RH and higher, however, crystallization to the trihydrate occurs rapidly; although over the 2-month period, crystallization was never complete. Assessment of chemical degradation by high-performance liquid chromatography analysis revealed significant instability at 21% RH; whereas at higher RH, the extent of chemical degradation was reduced, reflecting the greater crystallization to the more chemically stable crystalline form. It is concluded that when amorphous forms of salts occur in solid dosage forms, the simultaneous effects of enhanced water vapor sorption on crystallization and chemical degradation must be considered, particularly when assessing solid-state chemical degradation at higher temperatures and RH (eg, 40°C 75% RH)

Mechanism for Polymorphic Transformation of Artemisinin during High Temperature Extrusion

NoA novel, green, and continuous method for solid-state polymorphic transformation of artemisinin by high temperature extrusion has recently been demonstrated. This communication describes attempts to understand the mechanisms causing phase transformation during the extrusion process. Polymorphic transformation was investigated using hot stage microscopy and a model shear cell. At high temperature, phase transformation from orthorhombic to the triclinic crystals was observed through a vapor phase. Under mechanical stress, the crystalline structure was disrupted continuously, exposing new surfaces and accelerating the transformation process