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Techniques for ENHANCEMENT OF DISSOLUTION RATE

Department of Pharmaceutics | Sagar savale

Mr. Sagar Kishor Savale[Department of Pharmaceutics]

avengersagar16@gmail.com

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Contents INTRODUCTION

PROCESS OF DISSOLUTION METHODS TO ENHANCE DISSOLUTION RATE

CONCLUSION  

REFERENCES

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INTRODUCTION Dissolution “ Dissolution is the process by which a solid phase goes into solution”

Dissolution Rate “Dissolution rate may be defined as the amount of drug substance that

goes in to solution per unit time under standardized conditions of liquid-solid interface, temperature & solvent composition.”

Dissolution rate is given by Noyes-Whitney equation-

Under non sink condition dc/dt = KS (Cs-C) dc/dt =DS/h (Cs-C)

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Where , dc/dt = rate of drug dissolution, K= dissolution rate constant, S=surface area of the particle, (Cs-C)=concentration gradient, D= diffusion coefficient of drug in solution, h= thickness of diffusion layer. Under sink condition dc/dt =DS/h Cs

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Importance of dissolution study-

1) Necessary for predicting in-vivo absorption of drug.

2) Useful in product development.

3) Useful in Selection of excipient.

4) Help to study the rate of dissolution of drug.

5) Necessary for optimizing manufacturing process.

6) Useful in interpretation of solubility of poorly water soluble drugs.

Process of dissolution :

Process of dissolution : The process of dissolution involves breaking of inter-ionic or intermolecular bonds in the solute, the separation of the molecules of the solvent to provide space in the solvent for the solute, and the interaction between the solvent and solute molecule or ion.

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METHOD OF DISSOLUTION:

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Methods to Enhance Dissolution Rate Increase in the effective surface area of the drug. Particle size reduction Incorporation of surface active agents in formulation. Solute-Solvent Complexation reactions. Polymorphism. Molecular encapsulation with Cyclodextrins or Complexation with Cyclodextrins. Prodrug approach. Salt formation of drug.

Increasing the effective surface area of the drug : 

• Increasing the effective surface area of the drug The size of the solid particle influences the solubility because as particle becomes smaller, the surface area to volume ratio increases. The larger surface area allows a greater interaction with the solvent. The effect of particle size on solubility can be described by Where So is the solubility of infinitely large particles and S is solubility of fine particles, V is molar volume, γ is surface tension of solid and r is the radius of fine particle.

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Particle size reduction : • Particle size reduction Micronization technique:

Increasing dissolution by reducing particle size of poorly water soluble drugs. Reduction is done by variety of Micronization process such as grinding, ball milling, air attrition, utilization fluid energy mills. Micronization process usually results in 1-10µm diameter. Kronblum and Hirschorn evaluated two specific methods of Micronization, spray drying and air attrition, which provided drug forms of different specific surface areas and particle size ranges, as well as other physical characteristics.

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Incorporation of Surface Active Agents : 

• Surfactants can also be used to enhance solubility. A surfactant or surface active agent is amphipathic, meaning it has polar end (the circular head) and a nonpolar (the tail). When a surfactant is placed in water it will form micelles. A nonpolar drug will partition into the hydrophobic core of the micelle and the polar tails will solubilize the complex.  

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Solid Dispersions : • Solid Dispersions These are generally prepared by

solvent or co-precipitation method where by both the guest solute and the solid carrier solvent are dissolved in a common volatile solvent like alcohol. The liquid solvent is removed by evaporation under reduced pressure or by freeze drying which results in amorphous precipitation of guest in a crystalline carrier. Thus the basic difference between the solid dispersions and solid solutions/eutectics is that the drug is precipitated out later; e.g.: amorphous sulfathiazole in crystalline urea. Such dispersions are often called as Co-evaporates or Co-precipitates.

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Polymorphism : • Polymorphism The capacity for a substance to exhibit

in more than one crystalline form is polymorphism. If the change from one form to another is reversible, the process is called enantiotropy. Use of metastable forms help in increasing the dissolution rate.

Polymorphism A solid has a rigid form and a definite shape . The shape or habit of a crystal of a given substance may vary but the angles between the faces are always constant. A crystal is made up atoms, ions, or molecules in a regular geometric arrangement or lattice constantly repeated in three dimensions. This repeating pattern is known as the unit cell.

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The use of Metastable Polymorphs:

• The use of Metastable Polymorphs: The solid state characteristics of drug are known to potentially exert the significant influence on the solubility parameter. As the presence of metastable, polymorphic crystalline forms can exert a great influence on solubility, dissolution rate and biological activity of medicaments.

• Drugs which show met stability include Chloramphenicol, Prednisolone, Barbiturates, and Riboflavin.

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Molecular Encapsulation• Molecular Encapsulation with Cyclodextrins

(Complexation with Cyclodextrins) The α-, β-, γ- Cyclodextrins are cyclic oligosaccharides consisting of six , seven and eight glucose units respectively. Their important property is ability of forming inclusion complexes with smaller molecules which fit into their hydrophobic cavity of the Cyclodextrins. The formation of inclusion complex alters a variety of physico-chemical properties of the drug molecules such as its solubility, dissolution rate, membrane permeability, chemical reactivity and dissociation constant. Solubility increases with increase in the amount of cyclodextrin added.

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Prodrug Approach : • Prodrug Approach One method to increase the solubility

of a drug is to alter the structure of the molecule. The addition of polar groups like carboxylic acids, ketones and amines can increase solubility by increasing hydrogen bonding and interaction with water. Another structure modification may be can be to reduce intermolecular forces. E.g. : methyldopa (solubility ~10mg/ml) and methyldopa (10-300 mg/ml depending on pH). The addition of ethyl ester to methyldopa reduces the intermolecular hydrogen bond between the carboxylic acid and primary amine. There fore this addition reduces melting point and increases solubility.

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Salt form of the drug : • Salt form of the drug Most of the drugs are either weak

acids or weak bases. One of the easiest method to enhance dissolution rate of drugs is to convert them into salt forms. At a given pH, the solubility of a drug, whether acidic/basic or its salt form is a constant. The influence of salt formation on the drug solubility, rate of dissolution and the absorption can be explained by considering the pH of the diffusion layer and not the pH of the bulk of the solution. Consider a case of a salt of weak acid at any given pH of the diffusion layer of the salt of the weak acid will be higher than that observable with the free acid from the drug.  

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Nanosuspension : • Nanosuspension A Nanosuspension is a submicron

colloidal dispersion of drug particles which are stabilized by surfactants. The poor water solubility of drugs is major problem for drug formulation. To date, nanoscale systems for drug delivery have gained much interest as a way to improve the solubility problems. The reduction of drug particles into the sub-micron range leads to a significant increase in the dissolution rate and therefore enhances bioavailability. Nanosuspensions are promising candidates that can be used for enhancing the dissolution of poorly water soluble drugs.

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Ternary systems : • Ternary systems Hydrophilic polymers have been

commonly used as carriers for preparing solid dispersions. Among them, Polyvinylpyrrolidone (PVP) was widely employed for its high aqueous solubility, high physiological tolerance, and low toxicity. In recent years, the interest in incorporating a surface-active carrier into solid dispersion increased greatly and a high improvement in drug dissolution was reported.

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Conclusion : • Conclusion For any drug to show proper efficacy and safety it

should reach the systemic circulation showing optimum bioavailability that further depends upon the dissolution of the drug dosage form in vivo and this dissolution should be occurring at a required rate. The dissolution can be enhanced to improve the bioavailability. Using proper surfactants, increasing the surface area by reducing the particle size, etc, can enhance the dissolution and the above discussed parameters, thus improving bioavailability and therapeutic efficacy of the medicament. Dissolution depends on the chemistry of the active ingredients and physico-chemical properties of the excipients used.

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References : • D.M. Brahmankar, Sunil B Jaiswal. Biopharmaceutic and

pharmacokinetics 2005; pg no. 29, 290-296. Abdou. Dissolution of pharmaceutical drugs 2001; pg no. 5, 56-68.

• V. Venkateshwar Rao “Biopharmaceutic and pharmacokinetics 2005. Connors KA. The stability of cyclodextrin complexes in the solution. Chem Rev. 1997; 97:1325-1357.

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