FORMULATION AND EVALUATION OF AMOXICILLIN TRIHYDRATE MODIFIED RELEASE DOSAGE FORMS

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1.1.2.1 Ideal Characteristics of the Drug Candidate for Extended Release Formulation6

A.    Physiochemical Properties of the drug:
a) Aqueous solubility:

Lower limit solubility for such product is reported to be 0.1 mg/ml. As the drug must be in solution form before absorption, drug having low aqueous solubility usually suffers oral bioavailability problem due to limited GI transit time of undissolved drug and limited solubility at absorption site. So these types of drug are undesirable.

Drug having extreme aqueous solubility are undesirable for ER because, it is too difficult to control release of drug from the dosage form.

Physiological pH dependent solubility i.e. variation in solubility at different GI pH are undesirable (e.g. Aspirin, which is less soluble in stomach, but more soluble in intestine) as it will yield variation in dissolution rate. A drug with good aqueous solubility, pH independent solubility is desirable for oral new drug delivery system

b) Partition Co-efficient:
As biological membrane is lipophilic in nature through which the drug has to pass though, so partition co-efficient of drug influence the bioavailability of drug very much. Drug having lower partition co-efficient values less than the optimum activity are undesirable for oral ER drug delivery system, as it will have very less lipid solubility and the drug will be localized at the first aqueous phase it come in contact e.g. Barbituric acid.

Drug having higher partition co-efficient value greater than the optimum activity are undesirable for oral ER drug delivery system because more lipid soluble drug will not partition out of the lipid membrane once it gets in the membrane. The value of partition co-efficient at which optimum activity is observed is approximately 1000:1 in 1-octano/water system.

c) Drug stability in-vivo:
As most of ER Drug delivery system is designing to release drug over the length of the GIT, hence drug should be stable in GI environment. So drug, which is unstable, can’t be formulated as oral ER drug delivery system, because of bioavailability problem.
E.g. - Nitroglycerine.

d) Protein binding:
The Pharmacological response of drug depends on unbound drug concentration drug rather than total concentration and all drug bound to some extent to plasma and or tissue proteins. Proteins binding of drug play a significant role in its therapeutic effect regardless the type of dosage form as extensive binding to plasma increase biological half life and thus sometimes ER drug delivery system is not required for this type of drug.

e) Drug pKa& Ionization at physiological pH:
As we know only unionized drug are absorbed and permeation of ionized drug is negligible, since its rate of absorption is 3 to 4 times less than that of the unionized drug. pKa range for acidic drug where 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 shall be non-ionized at the site to an extent 0.1 – 5.0%. Drugs existing largely in ionized form are poor candidates for oral ER drug delivery system. e.g.:- Hexamethonium.

f) Mechanisms and sites of absorption:
Drug absorption by carrier mediated transport and those absorbed through a window are poor candidate for oral ER drug delivery system e.g. – several B vitamins. Drugs absorbed by passive diffusion, pore transport and through over the entire length of GIT are suitable candidates for oral ER drug delivery system.

g) Molecular size and diffusivity:
With large molecular size are poor candidate for oral ER drug delivery system because it the ability of the drug to diffuse polymeric membrane is a function of its diffusivity (or diffusion co-efficient). Diffusivity depends on size shape of the cavities of the membrane. The diffusion co-efficient of intermediate molecular weight drug i.e.-100 to 400 Dalton, through flexible polymer range from 10-6 to 10-9 cm2/sec. For drugs having molecular weight > 500 Daltons the diffusion co-efficient in many polymers are very less i.e. less than 10-12 cm2/sec. Drugs is very difficult to control release rate of medicament from dosage form e.g. proteins and peptides.

h) Dose size:
If a product has dose size >0.5gm it is a poor candidate for oral ER drug delivery system, because increase in bulk of the drug, thus increases the volume of the product.

B.     Biological Properties of Drug: -
a) Absorption:

For oral ER drug delivery system the rate of drug absorption (ka) should be more -API than that of the rate of drug release (kr) from the dosage form i.e. kr<<<ka. Drug that are slowly absorbed or absorbed with a variable absorption rate of elimination of drug are poor candidate for oral ER drug delivery system. Some possible reasons for a low extent of absorption are poor water solubility, small partition co-efficient, acid hydrolysis, and metabolism or its site of absorption.

b) Distribution:
Drugs with high apparent volume of distribution, which influence the rate of elimination of the drug, are poor candidate for oral ER drug delivery system e.g. Chloroquine.

c) Metabolism:
Drug, which extensively metabolized is not suitable for ER drug delivery system. A drug capable of inducing metabolism, inhibiting metabolism, metabolized at the site of absorption of first-pass effect is poor candidate for ER delivery, since it could be difficult to maintain constant blood level e.g. levodopa, nitroglycerine.

d) Half-life of drug:
A drug having biological half-life between 2 to 8 hours is best suited for oral ER drug delivery system. As if biological half-life < 2hrs the system will require unacceptably large rate and large dose and biological half-life >8hours formulation of such drug into oral ER drug delivery system is unnecessary.

e) Margin of safety:
As we know larger the value of therapeutic index safer is the drug. Drugs with less therapeutic index usually poor candidate for formulation of oral ER drug delivery system due to technological limitation of control over release rates.

f) Plasma concentration response relationship:
Generally pharmacological response of drug depends on plasma drug concentration rather than size and dose. But some drugs pharmacological activity is independent of plasma concentrations, which are poor candidate for oral ER drug delivery system. E.g. Reserpine.

g) Concentration dependency on transfer of drug:
Transfer of drug from one compartment to other by zero kinetic process then such drugs are poor candidate for oral ER delivery system, it should be first order kinetics.

1.1.2.2 Types of Extended Release Formulation6
Many current oral extended release systems are available
a)      Dissolution-controlled release system.
b)      Diffusion-controlled release system.
c)      Osmotic pump system.
d)     Erosion controlled release systems.

a)      Dissolution controlled release systems:
In dissolution controlled extended release systems the rate of dissolution in the gastrointestinal juices of the drug or another ingredients is the release controlling process. Sparingly water-soluble drug can form a preparation of a dissolution controlled extended release type. Reduced drug solubility can be accomplished by preparing poorly soluble salts or derivatives of the drug. An alternative means to achieve extended release based on dissolution is to incorporate the drug in a slowly dissolving carrier.

Dissolution controlled extended release systems can also be obtained by covering drug particles with a slowly dissolving coating. The release of the drug from such units occurs in two steps,
1.      The liquid that surrounds the release unit dissolves the coating (rate limiting dissolution step).
2.      The solid drug is exposed to the liquid and subsequently dissolves sustained release oral products employing dissolution as the rate limiting step are in principle the simplest to prepare.

A drug with a slow dissolution rate is inherently sustained. Some example of these drugs includes digoxin, griseofulvin, and salicylamide. Others, such as aluminum aspirin, ferrous sulfate, and benzphetaminepaomate, produce such forms when in contact with the absorption pool contents.

For those drugs with high water solubility and therefore high dissolution rate, one can decrease solubility through appropriate salt of derivative formation. Unfortunately, forms such as these do not meet the criterion of constant availability rate because their surface area decreases with time. Nevertheless, sustained drug release can be achieved by coating drug particles or granules with materials of varying thickness or by dispersing them in a polymeric matrix.

Principle:
If the dissolution process is diffusion layer controlled, where the rate of diffusion from the solid surface through an unstirred liquid film to the bulk solution is rate limiting, the flux J is given by:
J = -D (dc/dx)  ---------- (1)

Where D is the diffusion coefficient and dc/dx is the concentration gradient from the solid surface to the bulk solution. The flux can also be defined as the flow rate to material (dm/dt) trough a unit area (A), thus one has the equation:
J = (1/A) dm/dt ---------- (2)

If the concentration gradient is linear and the thickness of the diffusion layer is h,
dc/dx = (Cb – Cs)/h ---------- (3)

Where Cs is the concentration at the solid surface and Cb is the concentration in the bulk solution. By combining the above equation, the flow rate of material is given by
dm/dt = -(DA/h)(Cb–Cs) = kA(Cs – Cb) ---------- (4)

Where k is the intrinsic dissolution rate constant.

The above equation predicts constant dissolution rate. If the surface area, diffusion co-efficient, diffusion layer thickness, and concentration difference are kept constant. However, as dissolution proceeds, all of the, parameters the surface area especially, may change.

Figure 1.1: Dissolution control of drug release via thickness and dissolution rate of the membrane barrier coat.

Most suitable dosage forms for this mechanism is compressed tablets containing coated particles. E.g. Ethyl cellulose, Nylon, Acrylic resins. Release depends on drug solubility and pore structure membrane. Constant release resulted when GI fluid passes through barrier to dissolve drug.

b)     Diffusion Controlled Release:
There are basically two types of diffusion-controlled systems, which have been developed over the past two decades: reservoir devices and matrix devices. In diffusion controlled extended release systems the transport by diffusion of dissolved drug in pores filled with gastric or intestinal juice or in a solid (normally polymer) phase is the release controlling process.

Depending on the part of the release unit in which the drug diffusion takes place, diffusion controlled release systems are divided into matrix systems (also referred to as monolithic systems) and reservoir systems.

In matrix systems diffusion occurs in pores located within the bulk of the release unit, and in reservoir systems diffusion takes place in a thin water-insoluble film or membrane, often about 5-20 μm thick, which surrounds the release unit. Diffusion through the membrane can occur in pores filled with fluid or in the solid phase that forms the membrane.

Drug is release from a diffusion controlled release unit in two steps-
1. The Liquid that surrounds the dosage from penetrates the release unit and dissolves the drug. A concentration gradient of dissolved drug is thus established between the interior and the exterior of the release unit.
2. The dissolved drug will diffuse in the pores of the release unit or the surrounding membrane and thus be released, or, alternatively, the dissolved drug will partition into the membrane surrounding the dose unit and diffuse in the membrane.

Figure 1.2: diffusion release pattern

A dissolution step is thus normally involved in the release process but the diffusion step is the rate-controlling step.

The rate at which diffusion will occur depends on four variables:
*  The concentration gradients over the diffusion distance.
*  The area.
*  The distance over which diffusion occurs.
*  The diffusion co-efficient of the drug in the diffusion medium.

Some of these variables are used to modulate the release rate in the formulation.

c)      Osmotic pump system:
The rate of drug release in these products is determined by the constant inflow of water across semipermeable membrane into a reservoir, which contains an osmotic agent. The drug is either mixed with the agent or is located in a reservoir. The dosage form contains a small hole from which dissolved drug is pumped at a rate determined by the rate of entrance of water due to osmotic pressure.

The advantage of this type of product is that the constant release is unaltered by the environment of the gastrointestinal tract. The rate of release can modified by altering the osmotic agent and the size of the hole.

dm = Ak?ss    ---------- (5)
dt         h

Where, A =membrane area, k =membrane permeability, h =membrane thickness

Figure 1.3: Osmotic pressure controlled by size of hole and concentration of osmotic agent in the core system.

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