Melt extrusion and spray drying of carbamazepine and dipyridamole with polyvinylpyrrolidone/vinyl acetate copolymers.

AIM: Carbamazepine and dipyridamole are class II compounds (BCS) whose oral bioavailability is limited by poor solubility. The use of glass solutions to improve the bioavailability of this class of compound has been an area of research for a number of years. The influence of polymer parameters (Tg, hydrophilicity, solubility parameter, and ability to hydrogen bond) on glass solution properties is investigated. METHODS: Carbamazepine and dipyridamole glass solutions are prepared with PVP/VA 64 and PVP/VA 37 by spray drying and melt extrusion. The products are then characterized by XRPD, thermal, and spectroscopic methods. Yield, physical stability, and dissolution profiles are also assessed. RESULTS: The properties of the polymer greatly influenced the ability to produce glass solutions. With decreases in Tg and hydrophilicity, melt extrusion became the more viable of the two preparative techniques. Although glass solutions were successfully prepared, the greater the difference in component solubility parameter, the less physically stable the formulation. CONCLUSION: Consideration must be given to the characteristics of the polymer when selecting for glass solution formulation. Although a number of process parameters can be varied for melt extrusion and spray drying, their ability to overcome fundamental differences in the physical parameters discussed is limited.

Direct observation of single particle electrostatic charging by atomic force microscopy.

PURPOSE: To show that atomic force microscopy (AFM) can be used to directly study the electrostatic charging and dissipation of single pharmaceutical particles. MATERIALS AND METHODS: Particles of lactose attached to AFM cantilevers were charged on a glass surface at a relative humidity (RH) of 0.1%. By recording force-distance curves, we use a measurement of the long range electrostatic interaction to compare the generation of charge by contact charging and tribocharging and to study the effect of RH on charge dissipation. RESULTS: As expected, tribocharging by scanning the particle across the glass surface generates considerably more charge than repeated local contacts. Increasing the RH from 0.1 to 5% over a period of 37 min dissipates the tribo-generated electrostatic charge. CONCLUSIONS: Using a combination of the abilities of AFM to scan in contact mode and record force-distance curves, we have shown a novel method to study electrostatic charging of particles. By measuring the length of the long range electrostatic interaction, we are able to compare different mechanisms of generating charge and to study the effect of RH on charge dissipation.

Preparation of glass solutions of three poorly water soluble drugs by spray drying, melt extrusion and ball milling.

The aim of this study was to investigate the influence of the manufacturing process on the physicochemical properties of three poorly water soluble compounds (carbamazepine, dipyridamole, and indomethacin) when processed with a polymer (polyvinylpyrrolidone K30 (PVP)) at a 1:2 drug to polymer ratio. Melt extrusion, spray drying, and ball milling techniques were used to prepare glass solutions. Product homogeneity, dissolution, physical stability, and drug/polymer interactions were investigated. Particular attention was paid to solid phase analysis using XRPD, modulated temperature DSC, optical microscopy, and Raman microscopy and the importance of using a combination of techniques was demonstrated. The latter technique when applied to freshly ball milled samples exhibited the presence of drug and polymer rich areas, indicating that complete glass solution formation had not occurred. The three compounds produced products with differing physical stability with indomethacin proving the most physically stable. These differences in physical stability were attributed to hydrogen bonding of drug and polymer. The manufacturing technique did not influence physical stability, but it did affect dissolution. The dissolution of the spray-dried material was generally poor, compared to melt extruded and ball milled products. This was probably due to rapid dissolution of PVP from the small particles of the spray-dried products.

Single particle friction on blister packaging materials used in dry powder inhalers.

Using atomic force microscopy (AFM) the adhesion and sliding friction behaviour of single lactose particles attached directly to AFM cantilevers has been studied. Measurements were made on the two sides of a blister packaging material used in dry powder inhalers (DPI). Although no significant differences in adhesion were observed, clear differences in particle friction were evident, where one side offers consistently greater friction across the range of loads studied here. The packaging samples were characterised by time-of-flight secondary ion mass spectrometry (ToF-SIMS) and X-ray photoelectron spectroscopy (XPS) and found to have different surface chemistries. The observed difference in friction behaviour is discussed in the context of the differences seen in surface chemistry, topography and hardness. It is reasoned that in this case hardness has the largest influence, and on one sample soft surface layers are displaced by the particle. A clear relationship between friction and load was only observed with one of the three particles tested; this was attributed to multiple asperities being brought into contact, illustrating the important role of nanoscale contact geometry in determining friction behaviour.

A nanoscale study of particle friction in a pharmaceutical system.

Studies of single particle interactions in dry powder inhaler (DPI) formulations using atomic force microscopy (AFM) have recently grown in popularity. Currently, these experiments are all based on measuring particle adhesion forces. We broaden this approach by presenting a novel AFM friction study of single particles in a pharmaceutical system, to examine forces acting parallel to a surface. The sliding friction signal of lactose particles attached to AFM cantilevers was recorded in lateral force (LF) mode over 5 microm x 5 microm areas on five different surfaces chosen to represent both relevant inter-particle and particle-surface interactions. A ranking of friction forces was obtained as follows: glass approximately equal to zanamivir >zanamivir-magnesium stearate (99.5%/0.5%, w/w) blend approximately equal to magnesium stearate approximately equal to PTFE. The addition of magnesium stearate to the zanamivir surface dominated and significantly reduced the friction (Kruskal-Wallis test, P<0.001). AFM images of the contacting asperities of the lactose particles show changes in contact morphology due to two processes. Firstly the asperity wears flat due to abrasion and secondly small magnesium stearate particles transfer onto the asperity. It is proposed that in combination with AFM particle adhesion measurements, this method could be used to screen new formulations and the effectiveness of tertiary components in modifying carrier-drug interactions.

The influence of thermal and mechanical preparative techniques on the amorphous state of four poorly soluble compounds.

A number of studies in the literature have reported on the use of different preparative techniques to convert crystalline pharmaceutical compounds into the amorphous form. However, very few direct comparisons of different preparative techniques using the same drugs are available. The purpose of this study was to determine the influence of two techniques: quench cooling and ball milling on four structurally diverse pharmaceutical drugs. Dipyridamole, carbamazepine, glibenclamide, and indomethacin were converted to the amorphous form by (a) quench cooling of the drug melt and (b) ball milling. The chemical purity and physical form of the products was determined using diffractometric, spectroscopic, and thermal analytical techniques. Products were analysed immediately post preparation and after storage under different stability conditions. Quench cooling of the melt resulted in amorphous conversion of all four compounds. However with glibenclamide, quench cooling resulted in unacceptable chemical degradation whereas ball milling of glibenclamide resulted in a change in the keto-enol tautomerism at the aryl amide moiety of this drug. Ball milling resulted in predominantly amorphous products for all compounds except carbamazepine. Ball milling of carbamazepine resulted in a polymorphic transition of the starting material to form III. Physical stability studies showed that irrespective of preparative technique and storage conditions all samples showed at least partial reversion to the crystalline state after storage. Quench cooling of drug melts may be of use as a preparative technique however it can result in chemical degradation. Ball milling may also be of use as a preparative technique however its effectiveness is dependent on the unit cell structure of the compound.