FORMULATION OF AN ORAL MODIFIED RELEASEDOSAGE FORM OF AN ADRENERGIC DRUG

Albuterol, a sympathomimetic amine is a potent selective Beta adrenergic agonist. As a result it is used as a bronchodilator to treat chronic obstructive airway diseases in adults and childrens. The drug has a short half-life of 3-4 hours and must be administered 3-4 times daily to maintain a therapeutic concentration. This investigation was undertaken to study the in-vitro drug release characteristics of the marketed product under conditions that mimic in-vivo dissolution behavior. It was determined that the original marketed product released the initial dose in first half an hour and then the second dose after a period of 5-6 hours. High variability in drug release profiles were observed between various lots. It was decided to investigate the applicability of several new polymers and modern formulation techniques to provide similar but more reproducible release. To reproduce the extended release portion of the tablets, various concentrations of polymer and tabletting excipients were evaluated and an optimum formulation that provided near zero order release was determined. The formulation developed in the laboratory was scaled up to a production size batch. Various physical characteristics of the tablets were evaluated as specified in the USP XXII. Two different types of coating processes, the Accela-cota and fluidized bed coating apparatus (Aeromatic STREA I). were used to coat the tablets with an aqueous polymer latex dispersion to retard drug release from tablet cores for a period of 5-6 hours. These tablets were further coated with 2 mg of albuterol per tablet to provide the immediate

Albuterol is metabolized to a polar metabolite in humans, which has spectral and chemical properties different from the parent drug.
Albuterol is contraindicated in patients with cardiovascular disorders.
Teratogenic effects have been reported for albuterol in animals and oral administration of the drug has been shown to delay pre term labor6.B. Excipients obtained from natural origin is difficult to process and often prone to microbial contamination which in turn requires strict quality control testing before processing into a dosage form.
Organic solvents used in processing this materials are often hazardous.
The recovery of these solvents also adds to the manufacturing cost.

Controlled Release Dosage Forms
The term "Controlled release" has become associated with those systems from which therapeutic agents may be automatically delivered at a predetermined rate over a long period of time9. Products of this type have been formulated for oral, injectable, topical use and also include inserts for placement into body cavities9, IO. In general, controlled release delivery attempts to9: 1. Sustain drug action at a predetermined rate by maintaining a relatively constant, effective drug level in the body with concomitant minimization of the undesirable side effects often associated with the saw tooth plasma levels of single repeated dosage forms.
2. Localize drug action by spatial placement of the controlled release dosage form adjacent to or in the diseased tissue or organ.
3. Target drug action by using carriers or chemical derivatization to deliver drugs to a particular "target" cell type.
In practice, a very few if any of the applied systems embrace all of these activities. For the most part, these products focus on maintaining a constant drug level in the plasma. Theoretically, in a controlled release system, the rate of absorption should equal the rate of elimination. However, this is possible only by the use of an intravenous infusion. Thus, in practice alternative noninvasive routes such as oral, nasal and transdermal routes are preferred in attaining the therapeutic objectives of controlled release.

Oral Controlled Release Systems
Oral controlled release systems are popular because of convenient administration and reduced design constraintsB. Ideally, an oral controlled release preparation should immediately provide part of the dose at the absorption site to achieve a rapid therapeutic response. The remaining drug should be available at a rate sufficient to maintain the desired pharmacological activity9. Where A is the area, D is the diffusion coeffecient, Cs is the solubility of active drug in the matrix, Co is the total concentration in the matrix mt is the total amount of drug released at time t.

Repeat Action Tablets
A repeat-action tablet is one that provides the usual single dose of the drug immediately after administration and delivers the next single dose after a period of time. Repeat-action tablets are not true sustained release products. However, the dosage form is designed to extend the activity of the second dose of the drug often after the effect of the first dose has diminished. In this type of dosage forms the core ( \ serves as the base to which the initial dose is applied by usual coating techniques.
This type of dosage forms is prepared either by coating the immediate release portion of the drug over an enteric coated core tablet or by presscoating the initial dose over the core which has been coated with an enteric material. Figure 1. shows the schematic representation of dissolution process of a repeat-action tablets.

Albuterol Extended Release Tablets
Albuterol sulfate has been studied extensively and formulated into various types of dosage formsio.11.12,13. To date, the only controlled release oral dosage form available in the US market is albuterol sulfate repetabs7. The other oral dosage forms available in the market are conventional tablets, syrups and oral inhalations. These dosage forms are designed to deliver two or four mg orally or 90 µg per actuation for inhalation in a metered dose 7.

General Aspects of Coating
The process and techniques employed in the coating of tablets were inherited from the pill coating technique 15 and have been surrounded by secrecy. Tablet coating is a unit operation in which a layer of designed thickness of a suitable material sugar or film is cast around a compressed tablet core 13.
There are a number of various reasons for coating tabletsl3,14:     Poor uniformity in film thickness, results from uneven spraying of the film forming polymer. Drug release properties from the core may be altered due to porosity or thickness of the polymer film20.21.

Film Coating Materials
Since its introduction in the 1950's, film coating has undergone some radical change, both with respect to the equipment used for ......  Thus, aqueous film coating has become more acceptable and produced major benefits with respect to safety and cost. One potential drawback, however, when using aqueous coating is the relatively high latent heat of vaporization of water26. Thus one should anticipate that greater difficulty will be experienced in removing water from an applied film coating than that found with the previously used organic solvents. Concerns related to this issue are the potential for increased processing time, greater risk of temperature and moisture affecting drug stability, and opportunities for changes in drug release characteristics27,2s. In order to minimize these concerns, aqueous  the amount of water that has to be removed. As a result, a compromise has to be made between coating solid load, process time, product stability and the desired release characteristics28.

Processing Equipment
The choice of proper equipment and creation of a suitable processing environment is as essential to achieving a good film coating I \ as selecting an appropriate coating formulation2 9 . This is particularly true for aqueous film coating. Film coating requires a delicately balanced environment. The coating material must contain sufficient solvent to adhere properly and coalesce as it reaches the surface of the substrate, yet it also must dry rapidly and not be transferred from one tablet or particle to another. To create the necessary environment for this process to occur, specialized coating equipment is required.

Coating Pan
Over the past several decades, the design of coating pans have undergone major changes due to advances in coating technology and an increased demand for compliance with GMP's3I. Originally, pharmaceutical coating pans evolved from designs used in confectionery pan coating. However, it was obvious that aqueous film coating placed significant demand on the drying capabilities of the coating equipment. Designers of such equipment have made a variety of modifications to increase the interaction between the product being coated and the air responsible for removing solvent from that product.
In this regard fluid-bed equipment is considered as most effective31.32.
However, in spite of the advantages of the fluid-bed coating equipment, the so-called side vented pan has surfaced as the design of choice in most film coating applications. While a multitude of side vented pan designs exist, the basic principles are similar. The air is introduced into the interior of the pan, drawn through the product being coated, and exhausted to the exterior. Several of the approaches to air flow in the various types of side vented pans are shown in Figure   5.

Fluid-bed Coating Equipment
The fluid-bed or air suspension process has long been used in the coating of pharmaceutical solids. Equipment for this process was originally patented in the 1950's by Wurster32 . A schematic diagram of the Wurster fluid-bed coating process is shown in Figure 7.
During normal operation, fludizing air causes the product being coated to accelerate rapidly up through the inner partition which The Aeromatic fluid-bed coating equipment designs are versatile which operate on the same principles as the wurster process. This type of coating equipment has many added features and is designed to accommodate a variety of modular inserts such as dryer, spray granulator, aero-coater for bottom spray coating and ultra coater, bottom/tangential spray for tablet coating. Since these film coatings need to be highly functional, the benefits of the fluid-bed process, with its capabilities for applying coating uniformly with minimized particle agglomeration are readily evident and outweighs the side vented pan coating equipment in this regard.

USP Apparatus I
The USP basket method or apparatus I is the primary in-vitro dissolution testing equipment for conventional release dosage forms.
It was adopted as the first official method by the USP XVIII in 196943. shows the specification of the basket apparatus43.

USP Apparatus m (Reciprocating Cylinder)
In         Concentration (µg/ml) ( ( Actual percent of albuterol in each formulation was calculated using the following equation P = I 00 Xa/ 4 (wt/wa) wt is the theoretical weight in mg, wa is the actual weight of tablet composite used for the assay preparation.

UV Detection
Since the above described High Performance Liquid Concentration= Absorbance -0.0073/27.61 A typical standard curve for albuterol is shown in Figure 13. The results obtained from the two assay methods were compared and the difference was not significant. Hence the UV assay can be used for routine quality control measurements for the developed product.

Drug Release Studies of Marketed Product
In-vitro drug release from several lots of the marketed product was studied in various pH mediums in order to mimic the in-vivo dissolution behavior. The pH's selected were 0.

Laboratory Scale Manufacture
Various formulations of albuterol sulfate tablets were prepared in the laboratory by blending the drug. polymer and excipients in a specified order for a total time of 25 minutes using a turbula mixture.These blends were compressed using a carver laboratory press model-C to determine the initial parameters, such as formulation component concentration, blending time, hardness, tablet weight and drug release. The initial formulation components of three different formulations are shown in Table II.
The final formulation selected was scaled up to a batch size of one kilogram (-7000) tablets using a stokes single punch Fl press with 9/32" standard concave tooling. The fill volume in the lower punch of the tablet machine was adjusted to a theoretical weight of 135 mg and the compression force was adjusted to obtain a tablet hardness of 7-8 kilo pascals.

Particle Size Determination
Particle size of the ingredients used in hydrophilic matrix formulation can have significant impact on the performance and drug release characteristic56,57. In light of this logic, it was necessary to determine the particle size of the drug and the excipients used in the albuterol. Figure 14. shows the particle size distribution histogram for albuterol sulfate. The particle size ranged from 2 to 7 microns with a mean particle size of 3 microns. About 40 percent of the particles lie in the range of 2 to 5 microns which is fairly uniform. Figure 15.

Blending
Since the blending equipment used in the laboratory was not applicable for the large scale manufacture it was necessary to redetermine the optimum blending time using the half cubic foot V-Blender. In order to optimize the blending time five different lots were made by varying the total blending time from 30 minutes to 75 minutes.
Drug and excipients were added in specified order similar to ·that of laboratory scale manufacture, finally magnesium stearate was added as a lubricant and blended.  . Figure 19. HPMC Dispersed in Mineral Oil Plane Polarized Light ( 100 X) ( (

Built Density and Flow Properties
The bulk density of all the formulation components, and the tabletting blend was studied. A weighed amount of powder was placed in a 100 ml graduated cylinder and the volume occupied by the powder was determined. A preweighed quantity of powder was placed in a 100 ml graduated cylinder which was then tapped using a tap density apparatus (J. Engelsmann A.G. GmBH, Germany) at a constant rate of -500 taps and the fmal volume was noted as tapped density. These data together with the initial poured bulk and tapped densities were used to calculate flowability and the indices of compressibility derived by Hausner ( 1967) and Carr (1970)56. The drug excipient blend was placed in a powder funnel with a one centimeter diameter opening that was supported using a retard stand such that the bottom of the orifice was 10 centimeters from the bench surface. The powder was allowed to flow with the help of gravitational force and the angle of repose which is the angle(G) obtained between the free standing powder heap and the horizontal plane was measured.

Tabletting
The formulation developed in the laboratory was scaled up to a production size batch of 100,000 tablets. The drug, polymer and excipient blend was directly compressed into tablets using 9/32" standard concave tooling fitted in a Stokes 16 station instrumented rotary tablet press. The tablet weight and hardness was adjusted to 135 mg and -7 kilo pascals respectively. These tablets were later used for coating. The physical properties of the tablets were studied in accordance

.1 Preparation of Seal Coating Suspension
The Eudragit-S was dispersed in distilled water and a specified concentration of ammonium hydroxide solution was added to the Eudragit dispersion with constant stirring to effect the partial neutralization of the polymer55. A dispersion of talc in distilled water was prepared separately using a high speed dispersator. The talc dispersion was slowly added to the polymer latex suspension with constant stirring, plastisizer was added and the latex dispersion was thoroughly mixed.

.2 Preparation of Immediate Release Coating Solution
The coating solution for immediate release portion was prepared as follows. Hydroxypropylmethyl cellulose was dispersed in distilled water that had been preheated to 75-SQ<>C. The polymer solution thus formed was cooled to room temperature and a cold aqueous solution of albuterol sulfate was added and mixed thoroughly, finally plastisizer was added to this solution and mixed to obtain a homogeneous coating solution.

.3 Coating Procedure
A quantity equivalent to one kilogram (-7 400 tablets) of tablet cores was placed in the conical coating vessel of the fluidized bed apparatus and preheated for 3 minutes at 40°C, the fluidizing air pressure was set to 10 in a scale of 11. The coating suspension was sprayed continuously at a rate of 15 grams per minute using a peristaltic pump.
For the coating applied using the Accela Cota, a quantity equivalent to seven kilograms of tablet cores(-51, 000 tablets) was placed in the pan and preheated for 5 minutes at 40° C, the inlet and outlet temperatures were maintained at 55 ± 2°C and 35 ± 2°C. The pan was rotated at a speed of 12 RPM and coating suspension was sprayed continuously using a peristaltic pump at a rate of 36 grams per minute.
The tablets were further coated with an immediate release portion containing 2 mg of albuterol per tablet. The tablets were dried for 30 minutes at 400C at the end of the run in both the process.

Drug Release Studies for Developed Product
Drug release was studied using USP apparatus I and USP apparatus III. Six tablets were tested from each lot. The temperature of the dissolution medium was maintained at 37°C ± 0.5°C in all the dissolution experiments. For USP apparatus I were withdrawn automatically at appropriate interval samples with the help of a tris pump auto sampling unit. The quantity of albuterol dissolved was determined using a UV spectrophotometer at 226 nm 7. Similarly, the USP apparatus III was programmed such that the tablets were allowed to dissolve for a specified time at the specified pH in each row for a total period of twelve hours. At the end of the dissolution period a 5 ml sample was collected from each dissolution vessel with the help of a glass syringe fitted with 0 .22 µm membrane filter and samples analyzed in HPLC.

A. Variability in the Marketed Albuterol Tablets
Various physical characteristics of the Proventil tablets were studied in an attempt to determine the consistency in tablet weight, and content uniformity. It can be seen from the results in Table V that lot RDR-44 has the lowest coefficient of variation for average tablet weight.
The variability in weight may be due to the uneven thickness of sugar coat which is less consistent than the film coating54,55. The in-vitro dissolution of these lots of Proventil tablets were studied at various pH's in order to determine the amount of drug released in the specified time interval. The results for the two USP apparatus are presented in Table VI and VII and in Figure 20-21 for USP apparatus I and III respectively. The results show that the drug release from the tablet core is faster in USP apparatus III after 5 hours and slower in apparatus I. The faster drug

Design of Core Tablets
Based upon the above findings, a synthetic polymer with well defined release characteristics, which is soluble at pH higher than 6.8 was selected to seal coat the core tablets of the experimental formulation.
An aqueous film coating technique was used to coat both core and the immediate release portion.
In an attempt to match the drug release observed in the extended release portion of Proventil repetabs, various core formulations were made by directly compressing powder blends with different proportions of starch, lactose and hydroxypropylmethylcellulose plus albuterol sulfate (see Table IX),  This difference in release is due to the fact that polymer hydration is effected by increasing the concentration of soluble excipients57,59.
The physical characteristics of the tablets were evaluated for all the formulations. The bulk density data in

Evaluation of Physical Characteristics of Core Tablets
Parameters such as weight variation, hardness, thickness and friability must lie within an acceptable range for the tablets to be useful in providing the desired drug release and product characteristics. In addition, since these tablets would be coated for protection and to control drug release; it is important that the tablets withstand the physical stress encountered during the coating process39,42,45. Therefore, it is necessary to evaluate the physical characteristics of randomly selected tablets cores from each batch. After selecting formulation 468 as the final formulation a series of tablet lots (100,000 tablets) were made to evaluate the physical characteristics of these tablets under production conditions. Table XII shows the results obtained from these lots . The hardness falls within the expected range of 7 to 8 kpa for all the lots.
Friability was found to be less than 0.005 percent. All of the test batches passed the official testing for physical characterization of tablets as described in USP XXII.

C. Scale-up of Core Formulation to Full Scale Production
After selection of 468 as final core formulation for scale-up, a series of formulations were made while varying the total blending time to re-determine the optimum blending time needed for the large scale production. The results obtained for physical characterization and content uniformity of these formulations are shown in Table XIII. It is quite evident from the results of physical characterization of tablet that  Variability in weight and uniformity in drug content between tablets was found to be larger with drug release (see Table XIII    The processing parameters used for applying the seal coat using the Accela-cota is presented in Table XVII. After these processing parameters were determined the optimum coating thickness necessary to seal the core tablets and retard drug release for a period of 4 to 5 hours was (

E. Dissolution Studies
The Accela-cota was used to apply the seal coat and the immediate release coating. Tables XXII-XXIII and Figure 25 show the dissolution results for the final coated formulations as determined using USP apparatus I and III respectively. Since the total drug concentration was well below the saturation solubility, it was possible to maintain sink conditions for both of the dissolution apparatuses. The number of sampling intervals were limited in case of USP apparatus III due to the limited capacity of that instrument. The drug release is uniform and consistent for all the experimental formulations tested in both of the dissolution apparatuses. While drug release was slightly faster in USP apparatus III than that found in apparatus I, the difference was not significant at P<0.05 level. Interestingly, data presented earlier in this thesis showed significant differences in the mean percent released between various lots of Proventil tablets using USP apparatus I and III (see Figure 20-21).
The in-vitro drug release of the marketed product is highly variable, this in tum may be expected to have a significant effect on the in-vivo bioavailability. The drug release from the experimental tablets was found to be consistent with rapid release of the initial 2 mg of drug followed by a near zero order release of the second dose of 2 mg for period of 5-6 hours that was seen for the Proventil tablets. This second interval of drug release indicates that a steady state plasma level should be maintained. While the in-vitro drug release profiles of the experimental tablets are comparable to the marketed product and exhibit significantly less variability in drug release further clinical investigation  Accela-cota was found to be more efficient than the fluid bed coating ( process for applying the immediate release portion. However, the seal coat can be applied either of the two apparatus, But the Accela-cota is preferred due to its larger production capacity.
6 . The dissolution profiles obtained for the experimental formulations using the USP apparatuses I and III were found to be comparable. The drug release profiles for the experimental formulations were not significantly affected by the different dissolution methods and found to be uniform, consistent and reproducible.