poorly soluble drugs and solid dispersions

Taking advantage of the amorphous form– the preparation and characterisation of solid dispersions Rakesh Dontireddy, UCC, Cork

Outline Brief introduction to amorphous solids Solid dispersions Selected model drug and carrier Influence of drug:carrier ratio Influence of solvent composition Influence of processing parameters

crystalline A or h s m p o u

Crystalline state Amorphous state more stable good flow properties less hygroscopic relatively less soluble less stable poor flow properties more hygroscopic relatively more soluble Long range translational, rotational and conformational order No long range order, however may exhibit short range order Thermal behavior- well defined melting point Thermal behavior- glass transition point

Solid dispersions + Drug particles Carrier particles Disrupt molecular arrangements and supermolecular structures Create solid particles with altered molecular arrangements and supermolecular structure Create a molecular mixture of drug and carrier molecules Drug -Carrier solid dispersion particle s Diffusion in solution Mix melt of drug and carrier Cool molten mixture Remove solvent Dissolve or melt or melt and dissolve Techniques

Solid dispersions Solid solutions are a resultant single phase upon dispersion of two compounds in each other, at their molecular level Eutectic mixture Crystalline drug Amorphous carrier Amorphous drug Amorphous carrier Solid Dispersion Solid State Two phase solid system Single phase solid system Crystalline Amorphous Substitutional Interstitial

Pharmaceutical application Reasons for the increased dissolution rate Increased wettability due to dispersion in a hydrophilic carrier Reduced drug particle size and hence increased surface area in two phase solid dispersions Elimination of drug particles in solid solutions, drug is dispersed molecularly Reduced crystallinity or creation of amorphous systems

Model drug: Hydrocortisone practically insoluble in water, sparingly soluble in acetone and in alcohol, slightly soluble in methylene chloride solubility behaviour due to some hydrogen bonding capability due to the presence of both C=O and OH groups but largely due to dispersion forces Crystalline in nature Model carrier: PVP High water solubility – improve wettability and enhance dissolution High glass transition point – improve stability Amide group participates in hydrogen bonding

Influence of drug:carrier ratio on solid dispersion behaviour XRD patterns of spray dried dispersions (from 96% ethanol) of drug with different ratios of carrier

MDSC thermographs of PVP and spray dried dispersions (from 96% ethanol) of drug with different ratios of carrier showing the glass transition temperatures

MDSC thermographs of spray dried (from 96% ethanol) and Hydrocortisone unprocessed

Moisture content of dispersions spray dried from 96% ethanol (n=3)

40% PVP 50% PVP 60% PVP 75% PVP Moisture content of spray dried (96% ethanol)

Dissolution behavior of solid dispersions of spray dried dispersions (96% ethanol) of drug with different ratios of carrier (n=3)

Influence of solvent composition XRD patterns of spray dried dispersions prepared from a) 20% aqueous ethanolic mixtures and b) 96% ethanol with different ratios of carrier Influence of solvent behaviour on solid dispersion behaviour

MDSC thermographs of spray dried dispersions prepared from a) 20% aqueous ethanolic mixtures and b) 96% ethanol with different ratios of carrier showing the glass transition temperatures

Moisture Content of Spray Dried Systems (n=3)

Morphology of Spray Dried 20% Ethanol from Scanning Electron Microscopy Hydrocortisone 40% PVP 50% PVP 75% PVP

Dissolution behavior of solid dispersions of spray dried from a) 20% aqueous ethanolic mixtures and b) 96% ethanol with different ratios of carrier (n=3)

Influence of processing method + Drug particles Carrier particles Drug -Carrier solid dispersion particles Remove solvent Dissolve carrier and drug Process parameters Rate of solvent removal Temperature of material Humidity of air Volume of air Temperature of air etc

XRD patterns of both spray dried and freeze dried dispersions of drug and carrier at different ratios of carrier

Figure showing the MDSC scans of physical mixture ,spray dried HC sample and freeze dried HC sample

Moisture Content of Spray Dried and Freeze Dried Systems (n=3)

Hydrocortisone 40% PVP 50% PVP 75% PVP Morphology of Freeze Dried 20% Ethanol from Scanning Electron Microscopy

Dissolution Behaviour of Spray Dried and Freeze Dried Systems (n=3)

Conclusions: Drug:carrier ratio had a profound influence on the amorphosity Spray dried dispersions from both 20% ethanol and 96% ethanol solutions produced amorphous solids Spray dried dispersions from 20% ethanol solutions have higher Tg (greater stability???) Moisture content was higher for dispersions sprayed from 96% ethanol solutions Freeze dried dispersions showed a greater enhancement in dissolution rate compared to spray dried dispersions 75% w/w PVP freeze dried dispersions had the fastest dissolution rate of all dispersions prepared and also posses the highest glass transition temperature Freeze dried systems have higher Tg than both spray dried systems (Stability???)

Future work: Study the effects of storage conditions (temperature/humidity) on the stability of the amorphous dispersions Investigate further the impact of freeze drying conditions on performance of dispersions Further characterisation of dispersions by various techniques including DVS (Dynamic Vapour Sorption), IGC (Inverse Gas Chromatography), Surface area analysis Investigate further the relationship between moisture content of the dispersions and its effect on their glass transition temperature To measure the glass transition temperatures of samples using hermetically sealed crucibles Acknowledgements: Dr. Abina Crean, my supervisor, UCC, Cork Dr. Ann Marie Healy, TCD, Dublin

poorly soluble drugs and solid dispersions

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