Solid state manipulation
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The document discusses various techniques for improving the solubility and dissolution rate of poorly soluble drug compounds. It defines key terms like solubility, polymorphism, and solid dispersions. It describes three main methods for creating solid dispersions - hot melt method, solvent evaporation method, and hot melt extrusion. These methods aim to molecularly disperse the drug in an inert carrier in order to enhance solubility. The document also discusses other techniques like amorphous forms, solvates, and eutectic mixtures that can improve drug properties.
Solid state manipulation
- 1. Solid state manipulation Prem Patil M.Pharm+MBA (1st year)
- 2. Solubility Definition: Solubility is defined in quantitative terms as the concentration of solute in saturated solution at certain temperature, & in qualitative terms it can be defined as the spontaneous interaction of two or more substances to form a homogeneous molecular dispersion Solubility can be considered as the molecular dispersion of a solute in given solvent. Solubilization can be defined as the preparation of thermodynamically isotopic solution of a substance normally insoluble or very slightly soluble in a given solvent by the introduction of an additional component.
- 3. Process of solubilization It involves the breaking of inter-ionic or inter-molecular bonds in the solute, the separation of the molecules of the solvent to provide space in the solvent for the solute, interaction between the solvent and the solute molecule or ion. It can be better understood in 3 steps. 1. Holes open in the solvent. 2. Molecules of the solid breaks away from the bulk. 3. The free solid molecule is integrated into the hole in the solvent.
- 5. Solid state manipulation Many compounds, especially organic molecules will naturally occur or are available for being manipulated to exist in more than one form as solid. HOMOGENEOUS SOLID PHASE HETEROGENEOUS SOLID PHASE -CRYSTALLINE FORMS(POLYMORPHISM) -SOLVATES -NON CRYSTALLINE FORMS (AMORPHOUS) -RETARDATION OF PHASE TRANSFORMATION -DRUG DISPERSED IN MATRIX (SOLID DISPERSION, EUTECTIC MIXTURES)
- 6. Polymorphic modification: Polymorphism is often characterized as the ability of a drug substance to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattice. Solubility of each form depends upon the ability of the molecules to escape from the crystal to solvents. The stable from process the lower free energy at a particular temperature and therefore has the lower solubility or escaping tendency where as the meta stable forms posses higher free energy hence has higher solubility. About 50% to 100% increase in the dissolution rate can be achieved through polymorphic modifications. Ex. Chloramphenicol palmitate (form B) , Methyl prednisolone (form 2), chlor tetracyclin (form B).
- 7. Non-crystalline solutes (Amorphous) Amorphous solids consist of disordered arrangements of molecules and do not possess a distinguishable crystal lattice. As the term implies they will not contain internal crystal lattice structure. These are thermodynamically unstable. Amorphous solid forms give faster dissolution rates and higher solubilities than polymorphic modifications. E.g. Novobiocin Thus, the order for dissolution of different solid forms of a drug is Amorphous > Metastable > stable
- 8. Solvates (Pseudo polymorphism) Solvates are crystalline solid adducts containing either stoichiometric or nonstoichiometric amounts of a solvent incorporated within the crystal structure. The recrystallization of many drug substances from solution will results in the formation of solids containing solvent molecules as an integral part of their crystal structure. Majority of the cases crystalline materials referred as pseudo polymorphs, contain stoichiometric amount of solvents. Anhydrates > Hydrates Organic solvates > Organic non-solvates Enhances the solubility of drug markedly. Examples. Pentanol solvates of Fludrocortisone, Chloroform solvates of Griseofulvin, Cephalexin hydrate.
- 9. Retardation of phase transformation PVP, pectin, acacia, gelatin, methylcellulose, carboxy methyl cellulose, surfactants retard phase transformation. These materials retard phase transformation by; Inhibiting crystal growth by absorbing on to the surface of nucleated crystals or by Increasing viscosity which in tern retard the diffusion control process of crystallization. The retardation has improved physical stability of amorphous drugs by inhibiting drug crystallization or by minimizing molecular mobility.
- 10. Solid dispersion The term solid dispersion is applied to those system in which the dispersion of one or more active ingredients in a solid carrier solvents or matrix (hydrophobic), where the active ingredients could exist in solubilization amorphous states. Solid dispersions represent a useful pharmaceutical technique for increasing the dissolution, absorption and therapeutic efficacy of drugs in dosage forms. The most commonly used hydrophilic carriers for solid dispersions include polyvinyl pyrrolidone, polyethylene glycols, Plasdone-S630, Tween-80, Docusate sodium, Myrj-52, Pluronic-F68 and Sodium Lauryl Sulphate used. Examples: 1. Polyvinyl Glycols:- Oxazepam, Nifedipine, Ketoprofen 2. Polyvinylpyrrolidine:- Hydrochlorthiazide, Valdecoxib 3. Maltodextrins:- Piroxicam solid dispersions
- 11. : The term “solid dispersions” refers to the dispersion of one or more active ingredients in an inert carrier in a solid state, frequently prepared by the 1. • Hot melt mehod 2. …Continue • Solvent evaporation method 3. • Hot melt extrusion method
- 12. 1.Hot melt method(fusion method): The physical mixture of a drug and a water-soluble carrier was heated directly until it melted. The melted mixture was then cooled and solidified rapidly in an ice bath under rigorous stirring. The final solid mass was crushed, pulverized, and sieved, which can be compressed into tablets with the help of tableting agents. The melting point of a binary system is dependent upon its composition, i.e., the selection of the carrier and the weight fraction of the drug in the system.
- 13. 1. Hot melt method : Drug + vehicle (m.p low, organic solvent – insoluble) (heating) Melting . Freezing quickly Dosage forms A molecular dispersion can be achieved or not, depends on the degree of super saturation and rate of cooling used in the process. Important requisites : 1. Miscibility of the drug & carrier in the molten form, 2. Thermo stability of the drug & carrier. Suitable to drugs and vehicles with promising heat Suitable to drugs and vehicles with promising heat st stability.
- 14. 2.Solvent evaporation method The first to dissolve both the drug and the carrier in a common solvent and then evaporate the solvent under vacuum to produce a solid solution. This enabled them to produce a solid solution of the highly lipophilic β- carotene in the highly water soluble carrier polyvinylpyrrolidone. Many investigators studied solid dispersion of meloxicam15, naproxen and nimesulide using solvent evaporation technique.
- 15. 2. Solvent evaporation method: Drug + vehicle ( both soluble in solvent) organic solvent solution evaporate the solvent co-precipitates dosage forms The solvent evaporation can be done by spray drying or freeze drying. Temperatures used for solvent evaporation generally lie in the range 23- 65°C. suitable to drugs with volatility or poor suitable to drugs with volatility or poor s stability
- 16. 3.Hot-melt Extrusion: • Hot melt extrusion of miscible components results in amorphous solid solution formation, whereas extrusion of an immiscible component leads to amorphous drug dispersed in crystalline excipient. • The process has been useful in the preparation of solid dispersions in a single step.
- 18. Eutectic Mixtures When two materials are completely miscible in their molten state, they will solidify to form a eutectic mixture. At the eutectic composition, both drug and carrier exist In finely devised state, which results in higher surface area and enhanced dissolution rate of drug. The process of eutectic formation may cause the drug to crystallize in a metastable state. Urea and Succinic acid have been found to form simple eutectic with a wide variety of drugs.
- 19. REFERENCES: 1. D. J. W. Grant. Theory and origin of polymorphism. In H. G. Brittain (ed.) Polymorphism in Pharmaceutical Solids. Marcel Dekker, Inc., New York, 1999, pp. 1-34 2. Remington: The Science and Practice of Pharmacy, 21st ed., D. B. Troy, Ed., Baltimore, Maryland, USA: Lippincott Williams & Wilkins. 3. Review article, “Solid Dispersions : An Approach to Enhance the Bioavailability of Poorly Water-Soluble Drugs” by Sanjay Kumar Das, Sudipta roy. 4. Yalkowsky S. H, Joseph T. Rubino, Solubilization by cosolvents, Organic solutes in propylene glycol– water mixtures, Journal of Pharmaceutical Sciences, 1985; 74, 416-421 5. Fiese E.F, Hagen T.A. Preformulation. In: Lachman L, Liberman H.A, Kanig J.L, editors. The theory and practice of industrial pharmacy. 3rd ed. Bombay: Varghees Publication House, 1990; 171-196.
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