Date of Award


Document Type


Degree Name

Doctor of Philosophy (PhD)


Pharmaceutical Sciences

Research Advisor

James R. Johnson, Ph.D.


Hassan Almoazen, Ph.D. William McLaughlin, Ph.D. Arthur B. Straughn, Ph.D. George C. Wood, Ph.D.


Compression, Lutrol F68 micro, Micronization, Particle Agglomeration Inhibitors, Roller compaction, Spray drying


Micronization is one of the common processes for size reduction to increase surface area of poorly soluble Active Pharmaceutical Ingredient’s (API). This size reduction improves the dissolution rate and permeability thereby increasing the bioavailability for hydrophobic API’s.

Tablets and capsules are the most marketed and easy to manufacture solid dosage forms. During manufacturing of tablets, high compression forces are applied uniaxially on the powder bed to get a coherent consolidated compact with good tensile strength. So, diluents are required to mix with API’s and compress into tablets. When this mixture is compressed into tablets, there is a possibility of agglomeration of micronized API to API particles together within the tablet due to their high surface area and high surface free energy during compression. Increasing the particle size and decreasing the surface is generally expected to decrease the dissolution rate of the API.

Micronized furosemide and griseofulvin were used as model API’s based on the biopharmaceutical classification system to study the effect of compression force on particle agglomeration during compression and also to study the processes and materials to prevent that agglomeration. The size of furosemide and griseofulvin particles was measured after disintegration of tablets compressed by varying compression forces and drug loading. Effect of size of diluents on agglomeration of API’s was also studied by varying the size of diluents like lactose mono hydrate and dicalcium phosphate dihydrate. The bonding mechanism for formation of agglomerates of these API’s during compression was studied by comparing the tensile strength of the compacts soaked and dried in solvents of various dielectric media. Prevention of micronized particle agglomeration during compression was studied by using particle agglomeration inhibitors like PEG 3350, Lutrol F68 micro, hydroxyl propyl starch polymer and by various treatment methods like physical mixing, hexane slurry method, roller compaction and spray drying. The particles were characterized for change in crystal structure, polymorphism and surface morphology by X-ray diffraction, thermal studies and microscopy studies.

Micronized furosemide and griseofulvin particle size was increased significantly and linearly by increasing the drug loading and compression force during compression. The size of the formed agglomerates was directly proportional to particle size of diluents. The dominating bonding mechanism responsible for agglomerate formation was found to be solid bridge formation between drug particles during compression. The API to API particle agglomeration during compression was successfully prevented by using particle agglomeration inhibitors (PAI’s). Treatment with hexane and increase in the level of super disintegrant provided limited prevention of agglomeration during compression for furosemide particles. The spray drying with either mannitol or hydroxy propyl starch for micronized furosemide significantly reduced the agglomeration of API particles during compression. Roller compaction process with Lutrol F68 micro and PEG 3350 provided significant reduction in the agglomeration of drug particles for both the API’s during compression. Compression force and treatment with PAI’s on polymorphism was observed in changing the crystal structure and polymorphism during compression and confirmed by thermal and X-ray crystallographic studies for both the API’s. Scanning Electron Microscopy studies revealed compression force and roller compaction process with PAI’s changed the surface morphology of both the API’s.

The results of the above studies indicated that compression of micronized hydrophobic poorly soluble drugs into tablets affects the dissolution rate due to agglomeration of API. The micronization process for improving the dissolution rate of poorly soluble drugs showed disadvantageous with respect to tablets compressed at high compression forces because of agglomeration of furosemide and griseofulvin particles during compression. Hence control of particle size and selection of size of diluents are necessary during formulation of tablets of hydrophobic poorly soluble drugs. Primary particle size increase of micronized hydrophobic drugs during compression can also be minimized by treatment with particle agglomeration inhibitors prior to compression.