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Polymer solubility , solution solubility , diffusivity , thickness of hydrodynamic diffusional path length ,diffusional path thickness , loading dose ,surface area and other system parameters play varying degrees of rate limiting roles in controlling the release of drug molecules from various drug delivery system.

In the controlled release of a drug species from either polymer membrane permeation controlled drug delivery devices or other rate preprogrammed drug delivery devices, the drug molecule on the outer most surface layer of a drug particle dissociate from their crystal lattice structure, dissolve or partition into the surrounding polymer (in membrane or matrix form), diffuse though it, and finally partition into the elusion medium surrounding the drug delivery device.To release at an appropriate rate the drug requires adequate polymer solubility.The importance of polymer solubility in determining the rate of drug release from membrane permeation-matrix diffusion (membrane-matrix) hybrid and microreservoir type drug delivery system can be appreciated by examining equation. Q/t = CPK Dm / KDdhm + Dmhd Where CP = solubility of drug in the polymer phase. K= partition coefficient Dm and Dd are the diffusion in the polymer membrane with thickness hm and in the aqueous solution in the hydrodynamic diffusion layer with thickness hd. Q = [(2A Cp) CpDpt] 1/2 Equation indicates that, after a finite period of drug elution, a matrix diffusion controlled process become the predominant step in determining the rate release from the drug dispersing polymer matrix. Q= amount of drug release A= initial amount of drug loading dose Dp = diffusivity of drug in polymer Cp= solubility in polymer

And other equation: dQ /dt = ACpDp / [DpKm (1/Pm+1/Pd)] 2 + 4 ACpDpt1/2 On other hand, in the controlled release of drug from a polymer matrix diffusioncontrolled drug delivery system the magnitude of q\t values is a function of square root of the polymer solubility. The difference in polymer solubilites among drug is very striking for example: the solubility in silicone polymer can range from 1-2 g/ml to as high as 1511.8 g/ml This dramatic difference in polymer solubility among drug is very much dependent to the difference in chemical structure. Variation in functional group and their stereochemical configuration greatly affects the magnitude of the polymer solubility of drugs. Example: the polymer solubility of polyestrone in lipophilic silicone polymer is significantly reduced with the addition of one OH group. This varies in the axtent of reduction depending upon the position where as OH group is added. The polymer solubility of progesterone derivatives is further with the substitution of two or more hydroxyl groups. On other hand the estrification of these hydrophilic OH groups tends to improve the polymer solubility of steroids substantially. Polymer solubility can be increased by adding finely ground fillers e.g. silicone earth.If polymer is treated, microscopically as a solid solution, then the mole fraction solubility Cp of a drug in the polymer composition can be described by. Log Cp = (log Cp/Cp+Xp) Microscopically solution process of drug crystal in a polymer composition consists of two steps: a) Dissociation of drug from their crystals b) Solvation of these dissociated energy and drug molecules into polymer structure. The first step requires dissociation energy and is Tm dependent process. The second step requires a Solvation energy depend upon Ts, If this is the case, then the energy term in equation may be split as follows Log Cp =-log rp+ Hd/2.303 1/Tm- Hsp/2.303 1/Ts Hd is the energy required in the process of dissociation of the drug molecule from their crystal lattice structure. Hsp is the energy required in the process of solvation of drug molecules into the polymer structure.

Under controlled conditions both the log rp and Hd/2.303 term are constant values for a given drug species and equation can be reduced to equation to define the dependence the mole fraction polymer solubility Cp on the system temperature Ts, Log Cp = constant - (Hsp / 2.303 R )(1/Ts) Polymer solubility is dependent on Ts-1 Eg. : Dissolution of norgestomet in silicone polymer Hs = 6.60 Kcal / mole Log Cp = constant + (Hd /2.303 R)(1/Tm) Above equation suggest that mole fraction solubility Cp of drug species is exponentially dependent on the reciprocal of its melting point temperatureTm-1.

2) Solution solubility:
The solution solubility Cs affect the magnitude of drug release profiles from polymer membrane permeation controlled DDS. Study report: comparative study of the invitro release of various steroids from silicone capsules and found that the release rates in human plasma were 2-15 times greater than those in normal saline. This increase in the rate of steroid release was rationalized as the result of enhancement in the solubility of steroids in the elution medium binding. These studies also point to the importance of the solution solubility Cs in determing the rate of drug release from a drug delivery system. To gain a better understanding of the mechanisms of controlled drug release from membrane permeation, matrix diffusion , and micro reservoir type drug delivery systems, it is necessary to maintain a sink condition so that the release of drug is solely controlled by the delivery system and not affected by the solution solubility factor. The sink condition may be satisfactorily accomplished by: a) Maintaining the drug concentration in the bulk solution b) By using a water miscible cosolvent as a solubilizer and addition of cosolvent into the elution solution to increase the solution solubility of drugs. The aqueous solubility of most of the steroids is low. Therefore several pharmaceutical approaches can be applied to improve solubility of poorly soluble drugs such as Complexation, micelle formation, Co solvency etc.

Solubilization of poorly soluble drugs in aqueous solution can be effectively accomplished by using multiple cosolvent systems The apparent solubility of a steroid in various multiple cosolvent system is described by following relation:

1) Binary co-solvent system log Cx = log Cw + exfx . 2 ) Ternary system log Ca,x = log Cw + eafa + exfx 3) Quaternary system log Ca,b,x = log Cw + eafa + ebfb + exfx Cs--- are the apparent solubilites of a steroid in distilled water W. a,b,x = aqueous solution of various cosolvents

e = slopes for the semilograthmic relationship between solubility and the volume fraction f of a specific cosolvent. f = volume fraction of a specific cosolvent. The solution solubility dependence of drug release profiles is predictable from following equation. Q/t = CsDd /hd The magnitude of drug release rates Q/t from membrane matrix hybrid and microreservoir-type drug delivery devices should also be a function of drug solubility in an elution solution. Can be expressed alternatively as follows to define the effect of solution solubility Cs on the rate release from both membrane permeation and microreservoir type drug delivery systems: Log Q/t = log Dd / hd + log Cs Log Q/t = log (nmDd / hd ) + log Cs Eg: linear relationship between log Q/t and log Cs is given by norgestomet from silicon cap CRDDS.

In matrix type DDS; the effect of solution solubility on controlled drug release profiles is more complex in nature. Cs affects both mechanism and rate profile of controlled drug release from these systems. Q/t = KDdCs / hd or Q/t Cs

The controlled release of drugs from matrix type drug delivery prepared from hydrophilic polymer show dependence on Cs different from drug in that of devices prepared from lipophilic polymers. The effect of Cs is illustrated by release of norgestomet from Hydron implant. Thermodynamically, the dissolution of drug crystals in an aqueous solution is also energy dependent process. The temperature dependence of the solution solubility, as represented by mole fraction solubility Cs, is expressed by the relationship : Log Cs = (constant HTs/2.303 R)( 1/Ts) The linear relationship between Cs and Ts-1 is given by dissolution of norgestomet crystal in distilled water and various aqueous solutions of polyethylene glycol 400.

The interfacial partitioning of a drug molecule from polymer toward solution is related to its solubilites in polymer (Cp) and in solution (Cs) is defined by K = Cs / Cp = solubility in elution medium / solubility in Polymer composition The ratio of its solubility in the elution solution Cs over its solubility un the polymer composition Cp of the device, any variation in either the Cs or the Cp value result in an increase or decrease in the magnitude of the K value. Effect of K on controlled release of drugs from matrix type drug delivery system, both the mechanism and rate profile of drug release is dependent on variation in K. Eg. : Ethynodiol diacetate from matrix type silicone device. Q/t value increases linearly with the increase of partition coefficient.

Q = (kDdKCp/hd) t or Q = (kDdCs / hd) t

K = constant that accounts for the relative magnitude of the concentration gradient in both diffusion layer and depletion zone. When value of K is increased beyond critical point (K = 0.5) matrix controlled mechanism become predominant. Between partition control and matrix control region there exist a transition phase terms that is time at which drug release profile undergoes transition from partition controlled to matrix controlled process.

Ttrans= 32/ 1/KCs Where and =2ADp/ =ADphd/Dd Where and are the porosity and tortuosity of the polymer matrix. The dependence of the transition time on the partition coefficients can be appreciated can be appreciated by converting equation Log Kderivative= log K parent+ fg The attainment of a negative slope result from the fact that as alkyl chain length increases, polymer solubility of alkyl p- aminobenzoates is enhanced at the expanse of their solution solubility and the result is decreases in Kn.

The addition of hydrophilic functional group such as OH gr., to a drug tends to improve solution solubility with decreases in polymer solubilites, therefore results in increases in K. log KOH = log Kp + n oH

Kp and KoH = partition coefficient of progesterone and its hydroxyl derivative. n = number of OH groups is added oH = slope of (log KoH Vs n plots) Partition coefficient varies greatly from one type of biomedical polymer to another. The partition coefficient for derivative can be determined by log Kderivative = log Kparent + fg fg = value for all functional group and this equation shows the lipophilicity of a functional group. The magnitude of fg values varies from one type of functional group to another and also changes substantially as the functional groups moves from one position to another. Ex: on replacement of the methyl, fluoro or chloro group at position16 with a hydroxyl group. The hydrophilicity of corticosteroids increase at the express of lophophilicity.