Factors to be considered in the design of controlled release dosage form

Factors to be considered in the design of controlled release dosage form

Session Objectives

By the end of this session, students will be able to:

•       Enumerate the various factors to be considered in the design of CRDF

•       Explain the biological factors affecting drug candidate selection for CRDF

•       Discuss the physico-chemical attributes of a drug candidate in the design of CRDF

Physicochemical properties of a drug influencing design and performance of cdds

1)  Aqueous solubility

2) Partition coefficient and Molecular size

3) Drug stability

4) Protien binding

5) Polymer solubility (C_P)

6) Polymer Diffusivity (D_P)

7) Solution Diffusivity (D_S)

8) Thickness of polymer Diffusional path (h_P)

9) Thickness of hydrodynamic diffusion layer (h_d)

10) Drug loading dose (A)

11) Surface Area

Aqueous Solubility

Drug with good aqueous solubility, especially if pH-independent, good for controlled release dosage forms.

E.g.- pentoxyphylline.

Drug with pH-dependent aqueous solubility E.g.- Phenytoin or drug with  solubility in nonaqueous solvents E.g.- Steroids, are suitable for parentral (i.m.)  controlled release dosage forms

•       Good aqueous solubility with good dissolution rate.

•       so,the concentration in environment acts as driving force

•       Noyes Whitney equation gives the relationship between dissolution rate and aqueous solubility.

dc/dt = Kd A Cs

 

 

Where,

          dc/dt = dissolution rate

          Kd     = dissolution rate constant

          A       = total surface area of the drug

          Cs     = aqueous saturation solubility

•       Metronidazole - very low aqueous solubility

•       Enhancement solubility - Micelle formation, complexation, co-solvency, without chemical modification of drug molecules

Partition coefficient and Molecular size:

•       Influence permeability of the drug across the biological membranes  and rate controlling membrane

•       High partition coefficient(Oil soluble drugs) – readily penetrate but cannot proceed further

•       Low partition coefficient(water soluble drugs) – cannot penetrate the membrane

•       Hence, balance in K – permeation through biological and rate controlling membrane

•       The mechanism & the rate profile of drug release depends on the variation in the partition coefficient.

Ex. Controlled release of ethynodiol diacetate from matrix type silicone device.

The result shows that the magnitude of the the Q/t value increases linearly with the increase in the partition coefficient.

•       Drugs that have lower partition coefficient are not suitable for oral CR drug delivery system

•       Drugs that have higher partition co- efficient are also not suitable for oral SR drug delivery system as they will not partition out of the lipid membrane once it gets in the membrane.

Log K_n  = log k₀  - np_CH2

 Where

               K_n - partition coefficient for the compound with an alkyl chain length of n-CH₂ groups

               K₀ - Y intercept at zero carbon number,

         p CH₂ - slope of the log K_n versus n plot.

The attainment of negative slope -The effect of alkyl chain length on the magnitude of the partition coefficient alkyl chain increases - polymer solubility (C_P) increases - solution solubility (C_S) decreases - reduction in partition coefficient (K_n).

Addition of hydrophilic functional groups, such as –OH groups to a drug molecule tends to improve the solubility at the sacrifice of the polymer solubility in a lipophilic polymer.

Molecular size

•       Lower Mol. wt. faster and more complete absorption

•       More than 95% of drugs are absorbed by passive diffusion

•       Upper limit of drug mol size for passive diffusion-600 Daltons

Drug pKa and ionization at physiological pH

   pKa:

•       pKa – acid dissociation constant.

•       Aqueous solubility of weak acids and bases - pKa of compound and the pH of the solution or medium.

•       Acid drugs – acidic environment

•       Basic drugs – basic environment

•       Ionizable drugs must be programmed in accordance with pH variation across the GIT

•       Pka of drug is important for selection of polymer

•       Drugs existing largely in ionized form are poor candidates for oral Sustained  release drug delivery system

•       The pKa range for acidic drug whose ionization is pH sensitive is around 3.0-7.5  and pKa range for basic drug whose ionization is pH sensitive is around 7.0-11.0  are ideal for optimum positive absorption

Drug stability

•       Drug degradation – hydrolysis and/or metabolism

•       Drug in solid state undergo slower degradation than drug in suspension or solution.

•       Drugs - unstable in the stomach can be placed in a slowly soluble form or have their release delayed(enteric coated tab)  until they reach the small intestine

•       Drug – unstable in the intestine – different route of administration is chosen(floating tab)

•       E.g.: CDDS of Nitroglycerin - Nitroglycerine administered as sublingual tablet rather than oral tablet

Protein binding

•       Drug-protein binding serve as a depot for drug producing a prolonged release  profile, especially if high degree of drug binding occurs

•       The binding of the drugs to plasma proteins (eg.Albumin) results in retention of  the drug into the vascular space “the drug - protein complex” which can serves  as reservoir in the vascular space for sustained drug release to extra vascular  tissue but only for those drugs that exhibit a high degree of binding

•       Drugs + mucin = increases absorption

•       Charged compounds - greater tendency to bind

       E.g.: Diazepam and novobiocin – 95% protien binding

•       Extensive binding to plasma proteins - long half-life of elimination for drugs - most required property for a controlled release

Polymer solubility (C_P):

•       Drug release - drug particle dissociates from crystal, dissolve into surrounding polymer, diffuse through it.

•       Drug release at appropriate rate - adequate solubility.

•       Hence polymer solubility (C_P) can be seen in all the release rate equations of all types of controlled drug delivery systems.

•           Rate of drug release α polymer solubility (C_P)

•       Relationship between the drug release rate (Q/t) & the magnitude of polymer solubility (C_P) will be linear

Example:

Addition of –OH group to positions 11, 17 and 21 on the progesterone skeleton reduces the solubility of Progesterone in lipophilic polymer.

Esterification of –OH group increases the solubility.

Fillers (silicon earth) - increase the polymer solubility of drugs.

Polymer Diffusivity (D_P):

•       Diffusion of small molecules in a polymer structure -  energy activated process

•        Diffusant molecule moves to a successive series of equilibrium positions when it acquires activation energy for diffusion E_d,

•        The energy activated diffusion process is frequently described by the following Arrhenius relationship.

D_P = Do e ^-(Ed/RT)

    D_o is a temperature frequency factor

    E_d is the energy of activation of polymer for diffusion

E_d = E_b + E_r

   E_b   = The energy of Intramoleculer bending

   E_r  = The energy of intermolecular repulsion

   E_b - very high for short segment polymer chain - decreases as polymer chain becomes longer.

   E_r - increases as polymer chain becomes longer - degree of freedom becomes larger

During model calculation and diffusion measurements - molecular diameter of a diffusant - determining the magnitude of its polymer diffusivity

The polymer diffusivity of a diffusant molecule must be inversely proportional to the cube roots of its molecular weight

Polymer diffusivity D_P is also dependent upon the type of functional groups and their stereochemical position in diffusant

    The factors affecting polymer diffusivity D_P are –

 Cross Linking

•       D_P decreases - cross-linking of polymer increase.

•       cross-linking agent (ethylene glycol ,dimethyl acrylate)

 Effect of Crystallinity

•       LDPE has lower degree of crystallinity than HDPE

•       The crystallinity offers very low diffusion relative to the diffusion in the surrounding amorphous structure.

•        D_P  decreases when density of the PE membrane increases.

FILLERS:

Fillers (silica) are often incorporated into a polymer (silicone elastomers) to enhance its mechanical strength.

The presence of fillers was reported to affect polymer diffusivity than cross linking and effect of crystallinity.

Solution Diffusivity (D_S)

    The diffusion of solute molecules in a solution medium may be considered as a result of random motion of molecules.

    The solution diffusion process can be discussed by void occupation model & the theory of free volume. 

D_S=  D_o e ^-(En/RT)

            Where,

             D_S = solution diffusivity

                  D₀ = pre exponential factor

                  E_n= energy of activation for solution diffusion

          If solute molar volume ≥ molar volume of water then the diffusivity of the solute molecules in the aqueous solution (at 25⁰C) is inversely proportional to the cube root of molar volume.

 

When solution diffusivity of various chemical groups was compared on the basis of molecular volume, the relative rates found that,

    Alkane > Alcohols > Amides > Acids > Aminoacids > Dicarboxylic acids.

The diffusivity of solute molecules in an aqueous solution usually decreases as its concentration increase. This reduction is frequently related to the increase in viscosity that usually accompanies the increase in solution concentration.

The effect of viscosity (μ) is related to solution diffusivity (D_S).

D_S = w / μ

   Where,

          w is proportional constant.

Thickness of polymer Diffusional path (Hp)

•       The controlled release of a drug species from polymer membrane permeation & polymer matrix controlled drug delivery system - Fick’s law of diffusion.

•       Difference in the drug release patterns is a result of the difference in the time dependence of the thickness of their polymer diffusional path Hp

•       Reservoir type drug delivery devices with non-biodegradable and non-swollen polymers such as silicon elastomer. The h_P value is constant throughout the time span.

•       In matrix type drug delivery systems fabricated from biodegradable polymers the Hp in the polymer matrix as defined by the depletion zone grows progressively in proportion to the square root of time.

Non-biodegradable hydrophilic polymers - hydroxy ethylmethacrylate

Biodegradable polymers – polyhydroxy butyrate

Thickness of hydrodynamic diffusion layer (h_d):

•       Hydrodynamic diffusion layer H_d - drug release profiles when a device is immersed in stationary position in a solution, a stagnant layer is established on the intermediate surface of the device.

•       Thickness of this stagnant layer is dependent on solution diffusivity (D_s) and varies with the square root of times.

•       Diffusivity decreases - concentration increases.

•       Diffusivity reduction is frequently related to the increase in solution viscosity that usually accompanies the increase in solute concentration.

          

   Drug loading dose (A)

•       In the preparation of drug delivery device varying loading doses of drug are incorporated into the device as required for different lengths of treatment.

Q= [(2A – C_P) C_P D_Pt]^1/2

•       Variation in loading doses result only in a change in the duration of constant drug release profiles.

Dosage size

•       In general a single dose of 0.5 - 1.0 g is considered for a conventional dosage  form this also holds for sustained release dosage forms

•       If an oral product has a dose size greater that 500mg it is a poor candidate for  sustained release system, since addition of sustaining dose and possibly the  sustaining mechanism will, in most cases generates a substantial volume  product that unacceptably large

Surface Area:

·         The dependence of the rate of drug release on the surface area of drug device is well known theoretically and experimentally.

·         As the surface area increases, the rate of drug release increases in all types of CDDS

Summary

•       The physico-chemical factors affecting drug selection for CRDF are :

q  Dosage size

q  Partition coefficient and molecular size

q  Aqueous Solubility

q  Drug stability

q  Protein binding

q  Pka

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