FORMULATION OF AN ORAL CONTROLLED RELEASE DOSAGE FORM FOR NIFEDIPINE

Acknowledgements List of Tables List of Figures

In this study a method was developed to prepare control led release nifedipine tablets which would release the drug quickly and sustain the release for a longer period of time.
Solid dispersions of nifedipine with polyvinylpyrrolidone (40T) and polyethylene glycol 8000 were prepared to enhance dissolution and microporous polypropylene containing 75% void space was used to control the release to a desired level.
Various ratios of the two polymers were used. The results indicate that the solid dispersion technique is a good approach to enhance the dissolution of nifedipine.
However the polypropylene polymer used as a homogeneously dispersed matrix does not provide a zero -order release rate in low concentrations.
A preliminary study was also carried out to measure the    Nifedipine, a dihydropyridine derivative is one of a group of compounds thought to act by blocking the transmembrane inward movement of calcium. It has been shown to be an effective and relatively well tolerated treatment for stable, variant and unstable angina, mild to severe hypertension, and Raynaud's phenomenon (93).
Clinical trials support the view that nifedipine can be considered a first line choice in all grades of angina, especially when coronary vasospasm is the underlying cause or when hypertension and / or congestive heart failure are added complications. Nifedipine also appears to be particularly useful in clinical situations when a rapid lowering of elevated blood pressure is needed, and there is growing evidence that it is an effective and safe choice for the long term management of patients with mild to moderate hypertension (93).
However, the majority of data have been from medium term studies, and confirmation of its long term usefulness in well designed trials is still required. Additionally, it has convincingly been shown to be a useful adjunct to controlling blood pressure in patients refractory to conventional treatment with beta blockers, diuretics and various vasodilators (12,32). Nifedipine reduces the number, duration and severity of vasospastic attacks in more than 60% of ( patients with Raynaud's phenomenon of varying etiology, and in individual cases it apparently facilitates the healing of digital ulcers. Thus nifedipine is a worthwhile alternative to other drugs available for the treatment of the various forms of angina, acute episodes of hypertension, mild to severe hypertension (18,23,24,35,50,63,67,84,103) and Raynaud's phenomenon (22).

PHARMACOKINETICS :
Few well designed studies have been performed that adequately describes pharmacokinetic properties of nifedipine. The paucity of information detailing the kinetic aspects of nifedipine is due primarily to two factors (93 The ability of many compounds to crystallize in more than one crystal form is known as polymorphism and has been rewiewed by Haleblian (36). The solubility of each form depends on the ability of the molecules to escape from the crystal of the solvent. The stable form possesses the lower free energy at a particular temperature and pressure and therefore has the lower solubility or escaping tendency.
When a metastable form is placed in contact with solvents, it can rapidly undergo reversion to the more stable crystal form. The transformation process in such an environment will depend to a great measure on the degree of supersaturation achieved by the metastable material. There are also instances in which adsorbed water on the surface of the solid will catalyse the transformation process (87).
Using polymorphic modifications a 50 -100 % increase in dissolution rate can be realistically achieved (16,44,87). However for some drugs a four fold increase has been achieved (1,58). The amporphous form of novobiocin (69) and sulfa drugs (66,92) have been isolated and found to be much more soluble than the respective crystalline form. In case of novobiocin the amporphous form was 10 -fold more soluble than the crystalline drug (69

RACEMATES AND ENANTIOMERS
The racemates and enantiomeric forms of a compound may differ substantially in their solubilities (59,81). If, in addition to possessing higher solubility (and hence dissolution rate), an enantiomer is more active biologically than the racemate then attempts should be made to isolate the enantiomer and this should be used in the formulation.

REDUCTION OF PARTICLE SIZE
The effect of particle size reduction of drugs on their I dissolution rates and biological availability was reviewed comprehensivly by Fincher (25). A reduction in particle size of drugs leads to an increase in the total surface area (S) and the Noyes -Whitney equation predicts that this will result in an increase in dissolution rate. For drugs with poor water solubility a reduction in particle size generally increases the rate of absorption and /or total bioavailabili ty. For example, the therapeutic dose of griseofulvin was reduced to 50% by micronization (5) and a more constant and reliable blood level was produced. The commercial dose of spironolactone was also decreased to a fourth by just a slight reduction of particle size (56). Such enhancement of drug absorption could further be increased several folds if a micronized product was used (8,56).    with polyethylene glycols or PVP. Studies with these polymeric substances (14) indicate that the ratio of drug to polymer should be low to maximize the increase in dissolution of the drug. PVP is a noncrystalline polymer able in many instances to disperse a significant amount of a drug in a "high energy form" (61,83,91,95). The amount of drug which can be loaded into PVP as a high energy noncrystalline form is a function of the structure of the drug and the cosolvent used to prepare the coprecipitate (87). In some instances, the drug could be loaded into the polymer such that it would exist almost exclusively in the higher energy state as long as the ratio of drug to PVP was less than one (87).
Inhibition of the growth of the drug crystal structure by PVP in solid dispersions (20) has been linked to improved dissolution behaviour (19,90,92) and the formation of highly supersaturated drug solutions (19,62). The implication is that PVP prevents drug crystallization during preparation by a drug polymer interaction, possibly involving hydrogen bonding, in the liquid state (86,91). Once the solvent is removed, the interaction helps stabilize the amorphous high energy state ( 4 7).
The degree of solubilization observed for these systems ( is usually high. Reports of 6 to 10 fold increases in solubility is not uncommon. An interesting facet of these dispersions is that the high solubility achieved is maintained in solution for long periods of time (83,90,95).
High molecular weight PEG's which are highly crystalline in nature, are believed to be capable of entrapping low molecular weight compounds in their interstitial spaces (14). When PEG dispersions are prepared with their drug fractions greater than their "solid solubility", ultrafine suspensions of the drug are produced. Although these dispersions exhibit much faster dissolution rates than the pure drug, they are relatively slower dissolving than those dispersions containing the drug in its molecularly dispersed form. Another approach for dispersing drug on solid surfaces ( is the roll -mixing method of Nozawa et al (72,73). This method was shown to enhance the dissolution rate of phenytoin (72) and nifedipine (73).

COMPLEX FORMATION
The alteration of apparent solubility which can be achieved through complexation may be utilized to decrease or to increase solubility. The usefulness of the solid complex obtained will be dependent upon its apparent solubility relative to that of the inherent solubility of the substrate. For instance, Higuchi and Pitman (43)  An example of a system in which the use of solid complex has been found to substantially enhance dissolution rate is the digoxin -hydroquinone system (42). The dissolution rate of digoxin from the complex (two mols digoxin : three mols hydroquinone) was much more rapid and complete than that of digoxin when powders of equal mesh size and equal digoxin concentrations were compared.
Another example of enhanced dissolution rate through the use of complex is the 1:1 acetaminophen -caffeine complex (15). It was found that the solid complex at 25 degrees Celcius was a hexahydrate form. However, when the complex was dried to yield either the monohydrate or anhyd- This approach, however, is not without limitations.
Ironically, in some instances, it may be that rapid and total reversibility previously presented as an advantage may prove to be a problem especially in those cases in which ( ( dilution of a system may result in precipitation.
A second problem is the necessary presence of the ligand whose sensory and/or pharmacologic effects may be unacceptable.
Finally, in most reported cases, the apparent solubility increases realized by complexation were an order of magnitude or less (80). Consequently, when solubility increases of 10 2 or 10 3 are required, approaches other than complexation should be used. The basis for this strategy is that in order to dissolve, molecules must be removed from the crystal lattice. Any modification which reduces the crystal lattice energy, hence melting point, would tend to increase solubility (in all solvents). The relationship between the aqueous solubility Sw and melting point is expressed by the equation (3): where PC is the octanol/water partition coefficient and MP the melting point in degrees Celcius.

CONTROLLED RELEASE DOSAGE FORMS
A controlled release dosage form is generally defined as one that attempts to (57): (1) sustain drug action at a predetermined rate by maintaining a relatively constant, effective drug level in the body with concomitant minimization of undesirable side effects associated with a sawtooth kinetic pattern.
(2) localize drug action by spatial placement of a controlled release system adjacent to or in the diseased tissue or ( organ. (3) target drug action by using carriers ar chemical derivati zation to deliver drugs to a particular "target" cell type.
In practice, very few of the applied systems embrace all of these actions. In most cases, the release system These equations predict active agent release from a slab of thickness 1 where D is the diffusion coefficient, Mx is the total amount of active agent dissolved in the polymer ( and Mt is the amount released at a time t. As equation (3) shows, release rate decreases as t-1 / 2 over the first 60% of the release; over the remainder of the release the rate decays exponentially according to eq. (4).
When the active agent is dispersed in a the polymer, release kinetics have been derived by Higuchi (41): (5) where A is the area, Cs is the solubility of the active agent in the matrix and c 0 is total concentration in the matrix (dissolved plus dispersed) .
Although active agent release from monolithic systems does not proceed by zero-order kinetics, it is the simplest and most convenient way to achieve prolonged release of an active agent.
In a reservoir device the active agent is contained in a core that is surrounded by a rate controlling membrane.
Transport of the material in the core through surrounding nonporous, homogeneous polymer film occurs by dissolution at one interface of the membrane and then diffusion down a gradient in thermodynamic activity (39). It can be described by Fick's first law modified: Burst effects occur when during storage the active agent contained in the core saturates the membrane surrounding the core; then, when the device is placed in the desorbing medium, the active agent will rapidly desorb from the membrane.
Reservoir devices are capable of very long term zeroorder drug delivery. However they may require more complex fabrication procedures than monolithic devices. (

II. PURPOSE OF THIS STUDY
As can be seen from the preceding discusion, it would be desirable to formulate an oral solid dosage form, preferably a tablet, offering some degree of control over the release of nifedipine. The final properties will be influenced by the techniques used for enhancing the dissolution rate, by the material and proportion of the rate -controlling matrix, and by the tablet properties (hardness, disintegration, etc) .
For the enhancement of dissolution of nifedipine in the present study, the solid dispersion technique has been employed using PEG 8000 and PVP 40T as the polymer for forming coprecipitates. In a preliminary study Sugimoto et al (96) found that nifedipine -PVP coprecipitates gave the fastest release rates. Further, the molecular weight of PVP that gave the best results was 40,000. Compared to the bioavailability from a physical mixture (of nifedipine and PVP) the Cmax and AUC of the coprecipi tates were 5 -fold and 3fold higher.
The rationale for using PEG for preparing coprecipitates is the fact that the physicochemical stability of PEG coprecipitates are very high (99). The use of PEG 8000 for the preparation of nifedipine coprecipitates is not reported in the literature. However, Sumnu (98) found no significant differences between PEG 4000, 6000, and 10000 when release of nifedipine coprecipitates with these substances were compared. Granule Mixer, Turbula, Switzerland.

PROCEDURES
Nifedipine is quite light -sensitive and degrades rapidly on exposure to daylight, tungsten -bulb light, or standard fluorescent light. It is however, stable when "gold" fluorescent light is used (37). Therefore all procedures described here were carried out in a laboratory area which was either dark or had only gold fluorescent lighting.

TABLETTING
For preparing tablets the nifedipine -polymer coprecipitates were milled separately in a laboratory mill using a #20 screen. The two coprecipitates were then mixed in the desired ratio, according to the formulation (see table I    E. Disssolution studies.
A. EVALUATION OF THE ASSAY METHODS Table II summarizes the results obtained from the various mobile phases and flow rates used in developing a stability indicating assay HPLC assay for nifedipine.

HIGH PERFORMANCE LIQUID CHROMATOGRAPHY
The retention times for nifedipine and its photodecomposi tion product are denoted by Tr2 and Trl respectively.
The resolution R was calculated using the formula R = 2 (Tr2 -Trl)/ (Wl + W2) (7) where Wl and W2 are the base peak width of the degradation product and nifedipine respectively.
From the table it is evident that using 49% methanol in water as mobile phase gives the best resolution. Hence this (  was selected for the assay of nifedipine. A typical chromatogram is shown in figure 3. A linear relationship was found to exist between peak height (as well as peak area) and nifedpine concentration. Another problem with the HPLC assay was that it was very slow. For this reason it was used in conjunction with the UV assay described below.

ULTRAVIOLET SPECTROPHOTOMETRIC METHOD
The use of UV spectrophotometer at a wavelength of 238 nm provided a simple, relible and sensitive assay which was also rapid and reproducible. Detection was linear in the range of concentrations tested (O -20 mg/L). The absorbance (A) was related to the concentration (C) by the equation (see fig. 6): The coefficient of correlation r = 0.9998 To check for degradation of nif edipine during disso-1 u ti on or solubility studies, one of the three samples for   (Table III) Tables VI through IX and  degrees (96,98). The enhanced release of nifedipine from the four tablets is probably due to the presence of nifedipine in the amorphous form in the two coprecipitates. Although the exact physical nature of these dispersed systems was not investigated it is believed that reduction of particle size of the drug to the molecular and / or colloidal level is the primary contributing factor for this striking phenomenon (98) .
The increase in dissolution rate cannot be ascribed to   ( (   Table IX. Dissolution of tabletsa T3 and T4 under non -sink conditionsb.
-    Tables XIV and XV and figure 9 show the dissolution profiles of all the six tablets in "near sink" conditions.
Sink conditions are approximated when the volume of the dissolution medium is five to ten times the saturation volume of the medium (38). Since in our studies a fraction of the tablet equivalent to about 4 mg of nifedipine was taken, and since the solubility of nifedipine has been reported to be about 11 to 12 mg/L at 37 degrees (also seen          ( ( ( from figure 8), the volume of 1 liter of water taken in our studies was about 3 times the saturation volume. Hence it is appropriate to say that sink conditions were -nearly achieved in these studies.
From fig. 9 it can be seen that the dissolution rates of tablets not containing Accurel polymer increase in the order Tl < T2 < T3 = T4. The dissolution rates of tablets T3 (containing 25% PEG coprecipitate and 75% PVP coprecipitate) and T4 (containing 5% PEG coprecipitate and 95% PVP coprecipi tate) were not significantly different (P > 0.05) for 10, 20 and 30 minutes. For both of these tablets about 75% of the drug was released in the first 20 minutes. It was then decided to formulate a tablet which would release about 50% of the drug in 20 minutes but no more than 90% in 3 hours.
For this we chose to modify the formulation of T3 using Accurel polymer. our hypothesis was that addition of a small amount of this hydrophobic polymer would reduce the dissolution rate and bring it to the desired level.
In the first case (tablet TS) 5 mg of Accurel was added per tablet (total weight per tablet was 111 mg). As expected the dissolution rate decreased but still about 65% of the drug was released in 20 minutes and 93% was released in 3 hours.
In the second case (tablet T6) 7.5 mg of Accurel was