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Physicochemical properties:

Aqueous solubility and pKa:
A drug to be absorbed it must be dissolved in the aqueous phase surrounding the site of administration and then partition into the absorbing membrane. Two of the most important physicochemical properties of a drug that influence its absorptive behavior are its aqueous solubility and if it is a weak acid or base its pka. These properties pay an influential role in the performance of controlled release systems.

The aqueous solubility of a drug influences its dissolution rate, which in turn establishes its concentration solution and hence the driving force for diffusion across membrane.

Dissolution rate is related to aqueous solubility as shown by the Noyes-Whitney equation that, under sink condition is

dc/dt = KDACS


dc/dt  =  Dissolution rate
KD=  Dissolution rate constant.
A=  Total surface area of the drug particles.
Cs=  Aqueous saturation solubility of the drug.

The dissolution rate is constant only if surface area 'A' remain constant, but the important point to note is that the initial rare is directly proportional to aqueous solubility Cs

Therefore, aqueous solubility of a drug can be used as a first approximation of its dissolution rate. Drugs with low aqueous solubility have low dissolution rates and usually suffer oral bioavailability problems.

Aqueous solubility of weak acids and bases is governed by the pKa of the compound and pH of the medium.13

For weak acid.

St = So (1+ka/[H+]) = So(1+10 pH – pKa)…………...(1)

=  Total solubility (both ionized and un-ionized forms) of the weak acid  
=  Solubility of the un - ionized form
= Acid Dissociation constant
= hydrogen ion concentration of the medium.

Equation (1) predicts that the total solubility, st of a weak acid with a given pKa can be affected by the pH of the medium.

For a weak base,

St = So (1+[H+] / Ka = So (1+10 Pka – PH) ……………… (2)

= Total solubility (both conjugate acid and free base forms) of the weak base.
= Solubility of the free base form
= Acid dissociation constant of the conjugate acid.

So total solubility, St of a weak base whose conjugate acid has a given pKa, which can be affected by the pH of the medium.

In general, extremes in the aqueous solubility of a drug are undesirable for formulation into controlled release product. A drug with very low solubility and a slow dissolution rate will exhibit dissolution limited absorption and yield an inherently sustained blood level.

Formulation of such a drug into a controlled - release system may not provide considerable benefits over conventional dosage forms. Any system upon diffusion of drug through a polymer as the rate - limiting step in release would be unsuitable for a poorly soluble drug, since the driving force for diffusion is the concentration of drug in the polymer or solution, and this concentration would be low.  For a drug with very high solubility and a rapid dissolution rate, it is often quite difficult to decrease its dissolution rate to slow its absorption. Preparing a slightly soluble form of a drug with normally high solubility is, however, one possible method for preparing controlled release dosage forms.

Partition Coefficient
Between time that a drug is administered and the time is eliminated from the body, it must diffuse through a variety of biological membranes that act primarily as lipid like barriers.

A major criteria in evaluation of the ability of a drug to penetrate these lipid membranes is its apparent oil / water partition coefficient defined as

K = C0/CW

Co =  Equilibrium concentration of all forms of the drug
e.g ionized and unionized in an organic phase at equilibrium.
Cw = Equilibrium concentration of all forms in aqueous phase.

In general, drugs with extremely large values of ‘K are very oil soluble and will partition into membrane quite readily. According to Haunch correlation, the logarithm of the activity of a drug or its ability to be absorbed and the logarithm of its partition coefficient having parabolic relationship. The explanation for this relationship is that the activity of a drug is a function of its ability to cross membranes and interact with the receptor. 

The more effectively a drug crosses membranes, the greater its activity. The optimum partition coefficient value of a drug in which it most effectively permeates membranes and thus shows the greatest activity.  

The value of K at which optimum activity is observed is approximately 1000/1. Drugs with a partition coefficient that is higher or lower than the optimum is, in general, poorer candidates for formulation into controlled-release dosage forms.

Drug stability
One important factor for oral dosage forms is the loss of drug through acid hydrolysis and/or metabolism in the GI tract. Since a drug in the solid state undergoes degradation a much slower rate than a drug in suspension or solution. It is possible to improve significantly the relative bioavailability of  a drug that is unstable in the stomach, the most appropriate controlling unit would be one that release its content only in the intestine. The reverse in the case for those drugs that are unstable in the environment of the intestine, the most appropriate controlling unit in this case would be one that releases its contents only in the stomach, so, drugs with significant stability problems in any particular area of the GI tract are less suitable for formulation into controlled release systems that deliver their content uniformity over the length of the GI tract. Controlled drug delivery systems may provide benefits for highly unstable drugs because the drug may be protected from enzymatic degradation by incorporation into a polymeric matrix.

Protein Binding
There are some drugs which having tendency to bind with plasma proteins (eg. Albumin) and causes retention of the drug in the vascular space. The main force of attraction responsible for binding is wanderwals forces, hydrogen bonding and electrostatic forces. In general, charged compounds, because of electrostatic effects.

If a drug with protein then the distribution of the drug into the extravascular space is governed by the equilibrium process of dissociation of the drug from the protein. The drug-protein complex can serve therefore as a reservoir in the vascular space for controlled drug release to extravascular tissues, but only for those drugs that exhibit a high degree of binding. Thus, the protein binding characteristics of a drug can play a significant role in it's therapeutic effect, regardless of the type of dosage form.

Extensive binding to plasma proteins will be evidenced by a long half-life of elimination for the  drug and such drugs generally does not required a controlled-release dosage form, however, drugs that exhibit a high degree of binding to plasma protein also might bind to biopolymers in the GI tract, which could have an influence on controlled-drug delivery.

Molecular size and diffusivity:
Drugs in many controlled-release systems must diffuse through a rate controlling membranes or matrix. The ability of a drug to diffuse through membranes, it's so called diffusivity [diffusion coefficient), is a function of its molecular size (or molecular weight). An ; important influence upon the value of the diffusivity. 'D', in polymers is the molecular size for molecular weight) of the diffusing species. For most polymers, it is possible to relate logD empirically to some function of molecular size as

Log D = -Sv log V + Kv= - SM logM + Km
V=  molecuIar Volume.
M=  molecular weight.
SV,Sm,Kv, Km= constant

Pharmacokinetic Properties

The rate, extent and uniformity of absorption of a drug are important factors when considering it's formulation into a controlled - release system. Since the rate limiting step in drug delivery from a controlled-release system is its release from a dosage form, rather than absorption,

A rapid rate of absorption of drug relative to its release is essential if the 'system is to be successful. In case of controlled release dosage form Kr<<< Ka this becomes most critical in the case of oral administration. Assuming that the transit time of a drug through the absorption half-life should be to 4 hrs. This corresponds to a minimum absorption rate constant Ka of 0.17 to 0.23 hr necessary for about 80 to 95 % absorption over a 9 to 12 hr transit time. For a drug with a very rapid rate of absorption, (ie., Ka >>0.23 hr-1), the above discussion implies that a first order release rate constant Kr < 0.17 hr-1 is likely to result in unacceptable poor bioavailability in many patients. Therefore, slowly absorbed drugs will be difficult to formulate into controlled release systems where the criteria that Kr <<< Ka must be met.

The distribution of a drug into vascular and extravascular spaces in the body is an important factor in its overall elimination kinetics.

Two parameters that are used to describe the distribution characteristics of a drug are its apparent volume of distribution and the ratio of drug concentration in the tissue is that in plasma at the steady state called T/P ratio. The magnitude of the apparent volume of distribution can be used as a guide for additional studies and as a predictor for a drug dosing regimen and hence there is a need to employ a controlled-system.

Drugs that are significantly metabolized before absorption, either in the lumen or: tissue of the intestine, can show decreased bioavailability from slower-releasing dosage forms. Most intestinal wall enzyme systems are saturable. As the drug is released at a slower rate to these regions, less total drug is presented to the enzymatic process during a specific period allowing more complete conversion of drug to its metabolite. Formulation of these enzymatically susceptible compounds as prodrug is another viable solution.

Biological Half Life:
The usual goal of an oral sustained release product is to maintain therapeutic blood levels over an extended period. To this, drug must enter the circulation at approximately the same rate at which it is eliminated. The elimination rate is quantitatively described by the half-life.

Each drug has it's own characteristics elimination rate, which is the sum of all elimination processes including metabolism, urinary excretion and all other processes that permanently remove drug from blood stream. Therapeutic compounds with short half-life are excellent candidates for sustained-release preparations, since this can reduce dosage frequency. 

However, this is limited, in that drugs with very short biological half life as it may require excessively large amounts of drug in each dosage unit to maintain sustained effect, forcing the dosage form itself to become limitingly large.

Side Effects and Safety Considerations:
There are very few drugs whose specific therapeutic concentrations are known. Instead, a therapeutic concentration range is listed, with increasing toxic effects expected above this range and a fall off in desired therapeutic response observed below the range.

The most widely used measure of the margin of safety of a drug is its therapeutic index, (Tl).

TI =   –––––––

Where,  TD50 = median toxic dose
ED50 = median effective dose

For very potent drugs, whose therapeutic concentration range is  narrow, the value TI is small. In general, larger the value of TI, Usually are poor candidates for formulation into controlled-release product. A drug is considered to be relatively safe if its TI value exceeds 10.

Dose Size:
Since a controlled-release system is designed to alleviate repetitive dosing, it is naturally contain greater amount of drug that an corresponding conventional dosage form. For lose drugs requiring large conventional doses, the volume of sustained dose may be so large so to be impractical or unacceptable, depending on the route of administration. The same may be true for drugs that require a large release rate from the controlled-release system, e.g., drugs with shorter half-life. For oral route, the volume of the product is limited by patient acceptance.13

It was concluded that an oral sustained released dosage form offer many advantages for drugs having absorption from the upper gastrointestinal tract and improves the bioavailability of medications that are characterized by the narrow absorption window. A Gastro retentive sustained released floating matrix tablets was developed with polymers like HPMC (K4 M), K100 M and Xanthan gum.

1. Chien Y. W., “Novel Drug Delivery System” (IInd Edn), Revised and expanded, 1992,p.no.139-140.
2. Remington, “The Science and Practice of pharmacy”, 20th Edn, vol.I, p.no.903-913
3. Brahmankar  D. M. and  Jaiswal  S .B. in “Biopharmaceutics and Pharmacokinetics”, "A Treatise,” Vallabh Prakashan,   1st edn, 1995,p.no.347- 352.
4. Lee V. H., Robinson J. R. in ,“Sustained and Controlled Release Drug Delivery System ”  Marcel Dekker, New York, p.no. 71-121.,138-171
5. Lachman Leon, Liberman H.A.and Kanig J.L., “The Theory and Practice of industrial pharmacy” (3rd   Edn), Varghese publishing House Bombay,  p.no.430
6. RuggeroBettini, medfarm uniforit/pharmaco/itcis/Erasmus/erasm13,html[7k.
7. J. Lapidus, N. G. Lordi, in, “Journal Of Pharm. Sci.”, 1991-1992,(8), p.no 86.
8. Liberman, H. A. “Pharmaceutical Dosage Form; Tablets,” second Edn, Vol.  I,  p.no. 136.
9. Aulton M.E. “Hand Book of pharmaceutics Edition” 2001, p.no.291-295.
10. Howard C.Ansel “Pharmaceutical Dosage Form And Drug Delivery Systems”, (7th edition) p.no.229-243.
11. Jain N.K., “Controlled And Novel Drug Delivery” CBS 1-2, 2002,  p.no.676-698.
12. Roopa S. Ghirnikar, Yuen L. lee and Lawrence F. Eng , Spinal Cord Injury:Hope for a cure, Indian J.Pharm.Sci., 2001, 63(5), p.no. 349-363.
13. Yihong Qui, Howard Cheskin,” sustained release hydrophilic matrix tablets of zileuton : formulation and in vitro/ in vivo studies”, J. Cont. Rel., 1997(45),p.no.249-256


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