Pharmaceutical powder technology : towards a science based understanding of the behavior of powder systems

Microcrystalline cellulose is one of the most useful fillers for direct compression. Cellulose in general consists of an amorphous part and a crystalline part, which can exist in two polymorphic forms: cellulose I and cellulose II. UICEL (University of Iowa cellulose) is a cellulose II product and can be obtained by mercerization (chemical treatment with sodium hydroxide) from Avicel PH102®, a microcrystalline cellulose, which contains the cellulose I polymorph. X-ray measurements of the two substances confirmed the different polymorphic forms and demonstrated a higher degree of crystallinity for Avicel PH102® (73%) than for UICEL (64%).
The aim of the study was a comprehensive investigation of UICEL and Avicel PH102® concerning relevant properties in pharmaceutical technology.
The moisture content of powder samples stored over different saturated salt soluctions was measured gravimetrically. The resulting moisture soprtion isotherms were analyzed according to the BET (Brunauer, Emmett and Teller) and GAB (Guggenheim, Andersen and de Boer) equation. The latter proved to be valid over a larger range of relative humidity and should therefore be favored in order to describe the moisture content of excipients in dependency of the realtive humidity. The higher moisture content of UICEL compared to Avicel PH102® could not unambiguously be ascribed to the different polymorphic form of the crystalline part, since the higher amorphous fraction in UICEL results in a higher surface area, which is availiable for water molecules.
UICEL and Avicel PH102® were compressed with the Zwick® 1478 Universal Testing Instrument in a pressure range of 1-111 MPa. The compression characteristics off the two monosubstances were described according to the well-known Heckel and modified Heckel equation. Thereby, the modified Heckel equation turned out to be clearly superior compared to the Heckel equation. The fitting parameters K (Heckel equation ) and CE (modified Heckel equation) for both "in die" data and "out of die" data clearly indicated that UICEL is less ductile compared to Avicel PH102®. This difference is most likely caused by the different polymorphic form, because considering the higher moisture content and the higher amorphous fraction, a higher ductility would be exptected for UICEL. After compression, UICEL has furthermore a significant greater tendency to recover elastically, especially when compressed at high pressures.
Tablets prepared of UICEL showed remarkable disintegration properties, which differed significantly from tablets consisting of Avicel PH102®: The disintegration time was shorter for UICEL and almost independent of the realtive density of the tablet. The force, which is responsible for the disintegration was measured using the Zwick® 1478 Universal Testing Instrument. The maximum force as well as the rate of force development was much higher for UICEL compared to Avicel PH102®.
Measuring the swelling capacity, water uptake, pore structure of tablets and surface free energy, the attention was consequently focused on the question, why UICEL is acting as a disintegrant. Thereby, it could be shown that the water uptake for tablets consisting of UICEL was less dependent on the relative density of the tablets compared to Avicel PH102®. Considering the extremely small swelling capacity of both UICEL and Avicel PH102® particles, an increase of the intraparticle volume could not provide a possible reason for the water uptake, which must therefore be explained by an increase of the interparticle volume within the tablet. The pore size of UICEL tablets measured by mercury porosimetry, was higher by a factor of 2-3 over the whole relative density range compared to Avicel PH102® tablets. The surface free energy was measured by water sorption and inverse gas chromatography (IGC). The results fo both methods indicated that UICEL has a smaller surface free energy (polar and dispersive component) than Avicel PH102®.
Concerning UICEL, it was concluded that the small ductile behavior under pressure and the high elastic recovery result on the one hand in a higher pore size, which favors the fast water uptake (essential for disintegration) and on the other hand in a smaller binding surface area between two particles. The small binding surface area combined with a lower surface density of binding sites - suggested due to the lower surface free energy - effects a faster separation of the particles and thus a faster disintegration of the tablet. Additionally, the regeneration of the original shape of compressed UICEL particles upon water contact, is supposed to favor the disintegration process.
The feasibility of UICEL as a disintegrant was examined. The dissolution profile of proquazone from tablets consisting of a binary mixture of proquazone and a disintegrant (sodium starch glycolate (Vivastar®), pregelatinized starch (Starch 1500®), microcrystalline cellulose (Avicel PH102®) and UICEL) was measured spectrophotometrically in a flow-through system. A new biexponential equation could excellently describe the release of proquazone. Related to the efficiency of drug release, the used disintegrants could be ranked in the order: Vivastar® > UICEL = Starch 1500® > Avicel PH102®. Due to its good compactibility and flowability properties, UICEL is very well suitable as multipurpose excipient with the combined function as disintegrant and filler for direct compression. Vivastar® is very effective as disintegrant, but cannot be recommended as a filler. However, in order to use UICEL as disintegrant in more realistic multicomponent systems further investigations have to be performed.
Due to the higher moisture content of UICEL, the question raised whether incompatibility problems could occur when combined with moisture sensitive drugs. Thus, the decomposition of acetylsalicylic acid in a binary mixture with UICEL and Avicel PH102®, respectively was investigated at various conditions (temperature, relative humidity) over various time periods. However, despite the higher moisture content, the decomposition of acetylsalicylic acid was for all selected storage conditions smaller in combination with UICEL instead of Avicel PH102®. It was concluded that differences in the surface properties and in the overall surface area of the two celluloses cause the difference in drug stability.