Sustained released dosage form

An Assignment On Sustained released dosage form

Sustained released dosage form: Sustained released dosage form is a kind of dosage firm which is designed to achieve a prolonged therapeutic effect by continuously releasing medication over a prolonged period of time after administration of a single dose.

In this type of dosage form it is designed to deliver an initial therapeutic dose of the drug“loading dose” followed by a slower and constant release of drug. The rate of release of the “maintenance dose” is designed so that the amount of drug loss from the body by elimination is constantly replaced. With the sustained –release product a constant plasma drug concentration is maintained with minimal fluctuation.

Figure: Sustained release film coating tablet

Why we should go for coating formulation: If the followed questioned are answered concomitantly then one should go for film coating.

(a)  Is it necessary to mask objectionable color odor and taste?

(b) Is it necessary to control drug release?

(c)  What tablets size shape or color constraints must be placed on the development work.

Ideal requirements of film coating material:

(a)  Solubility in solvent of choice for coating preparation

(b) Solubility requirement for the intended use ex: free water solubility, slow water solubility, or PH dependent solubility.

(c)  Capacity to produce an elegant looking product.

(d)  High stability against heat, light, moisture , air, and the substrate being coated.

(e)  No inherent color, taste or odor.

(f)   High compatibility with other coating solution additives.

(g)  Non-toxic with no pharmacological activity.

(h)  High resistance to cracking.

(i)   Film former should not give bridging or filling of the debossed tablet.

(j)   Compatible to printing procedure. 

Materials used in film coating: 

Materials used in film coating includes: film forms, solvents, plasticizer, colorants etc.

Film former:They are dissolved inorganic solvent or dispersed in aqueous medium. Ex: Cellulose derivatives: It includes; HPMC (Hydroxy Propyl Methyl Cellulose), EC (Ethyl Cellulose) Povidone, Sodium Carboxy Methyl Cellulose etc.

Plasticizers: Plasticizers are generally added to film coating formulations to modify the physical properties of the polymer to make it more usable. One important property is their ability to decrease film brittleness.

Examples of plasticizers are polyols, such as polyethylene glycol 400, organic esters, diethyl phthalateoils/glycerides, such as fractionated coconut oil.In general, only water-miscible plasticizers can be used for aqueous-based spray systems.

Colourants: Any permitted colorants in a film coat formula are invariably water-insoluble colours (pigments). Pigments have certain advantages over water-soluble colours: they tend to be more chemically stable towards light, provide better opacity and covering power, and optimize the impermeability of a given film to water vapor. Examples of colourants are: iron oxide pigments,titanium dioxide, aluminum Lakes etc.

Solvents: The primary function of a solvent system is to develop or disperse the polymers and other additives and convey them to the substrate surface. Modern techniques now rely on water as a polymer solvent because of the significant drawbacks that readily became apparent with the use of organic solvents.

The most widely used solvents either alone or combination are water, ethanol, methanol, isopropanol, chloroform, acetone, methyl acetone, methyl chloride etc.

Significance of sustained release dosage form:

Ø  Reduction in drug blood level fluctuation: By controlling the rate of drug release peak and valleys of drug blood levels are eliminated. Highly fluctuating blood concentration of drug may produce unwanted side effects in the patients.

Ø  Frequency reduction in dosing: Extended release products deliver frequently more than a single dose of medication and thus they may be taken less often than conventional forms.

ØEnhanced patient convenience and compliance: With less frequency of dose administration a patient has a less chance to miss a dose.

Ø  Reduction in adverse side effect: Because there are fewer drug blood level peaks outside the drugs therapeutic range and into the toxic range adverse effects occur less frequency.

Ø  Reduction in overall health care cost: A single dose of sustained release product may cost less than an equivalent drug dose given several times a day in rapid release tablets. For patients under nursing care the cost of nursing time required to administer medication is decreased if only one drug dose is given to the patient each day.

Types of equipment use for sustain release film coating: Three general types of equipments are available for coating.

1. Standard coating pan: e.g., Pellegrino pan system, Immersion sword system, Immersion tube system

2. Perforated pan system: e.g., Accela cota system, Hicoater system, Glattcoater system, Driacoated system

Perforated pan system: Pan Coating is among the oldest industrial processes for forming small coated particles or coated tablets. Active cores ~2mm and larger are cascaded through a spray region within a rotating perforated pan. Drying air is directed through or over the cascading bed of material as atomized coat solution or suspension spray is directed at the rapidly passing product. Spray rate, atomized spray pattern, spray gun distance from the bed, pan speed, temperature, and airflow are adjusted for optimal coating efficiency. This technology is most commonly used for coating of tablets or other similarly size materials. Perforated pan system includes (a)Accela-Cota, (b) Hi- Coater (c) Driacoater (d) Glatt Coater etc.

Accela-Cota and Hi-Cota System: In Accela-Cota and Hi-Cota system drying air is directed into the drum, is passed through the tablet bed, and is exhausted through perforation in the drum

Figure: Accela-Cota System.

                                      Figure: Hi Cota System

Driacoter System: The Dricoater introduces drying air through hollow perforated ribs located on the inside periphery of the drum

                                       Figure: Dria coater pan

As the coating pan rotates the ribs into the tablet bed and drying air passes up through and fluidizes the tablet bed. Exhaust is form the back of the pan.

Glatt Coater: This is the latestperforated pan coater. In the Glatt Coater drying air can be directed from inside the drum through the tablet bed and out an exhaust duct; alternatively with an optional split-chambered plenum, drying air can be directed in the reverse manner up through the drum perforations for partial fluidization of the tablet bed. Several airflow configurations are possible.

                                             Figure: Glatt Coater

In all four of these perforated pan system the coating solution is applied to the surface of the rotating bed of tablets through spraying nozzles that are positioned inside the drum

Cause of perforation on the pan: The first coating pan rotating on a horizontal axis equipped with tapered side walls and an integral baffle system was introduced by Pellegrin and is well-known as the Pellegrinipan . The side walls of this pan are shaped with a pronounced taper, which increases the efficiency of particle movement by forcing the cores into an additional lateral movement. This results in a composite core movement yielding improved exposure of the core to the coating material.

The problem of using baffles and blades lies in the increased risk of friction between the core material and the pans, potentially resulting in increased amounts of dust formed during the coating process.

Hence, inventors havefocused on the implementation of perforated pans to improve the air transport in the core bed and consequently to increase the mixing and drying efficiency

Advantage of perforated pan coating system: Perforated pan coaters are efficient drying system with high coating capacity, specially in sustained release dosage form, and can be completely automated for the preparation of this type of dosage form.pan coaters offer low mechanical stress to the cores and provide the required motion of the core bed during the coating process.

Optimization of sustained release film coating formulation: The optimization of fim coating formulation may be necessary to improve adhesion of the coting to the core material to decrease bridging of intagliations, to increase coating hardness or to improve any other property that the formulator deems deficient. The development scientists have to consider three major factor which can affect the film quality.

(a)  Tensile strength of the film coating formulation (mainly dependent on polymer properties)

(b) Elasticity of the resultant film (mainly dependent on properties and quantity of plasticizer used.

(c)  And the film tablet surface interaction (each and every ingredient used in the coating formulation can effect this interaction and can change the adhesion properties of the film on the tablet surface.

Due to these important factors it becomes very important to use the most optimized coating formulations in order to get the best results for sustained release products.

During coating of sustain released film coating tablets by perforated pan system different parameters may have an impact on the final production. Thus optimization is necessary in this case. For example by optimizing spray rate, atomizing air pressure, distance between tablet bed and spray gun, inlet air temperature, pan differential pressure, pan speed (RPM), percent of solid content we can get better product.

Thus studies were done in optimization of non-aqueous film coating parameters.

Studies in optimization of non-aqueous sustained release film coating parameters:The purpose of this research was to study the non-aqueous film coating of tablets utilizing a laboratory scale perforated coating pan apparatus. The Spray rate, atomization air pressure, distance of nozzle from tablet bed, inlet air temperature, pan differential pressure, pan speed and % solid content these affect on final film quality of coated tablets. The process parameters related to perforated pan coating process can be identified and optimized

Opaspray blue O2K53395 (colorcon) was used as a coating material. The coating weredone by pan-coating equipment (Gansoncota, Ganson Ltd). The core tablet composed of lactose (Lactose India Ltd), starch ( Universal Starch co.), magnesium state (Nikita Chemicals co.).

The tablet were coated with use of perforated coating pan equipment. Inlet air flow, exhaust air flow & pan differential pressure was kept constant at 100 cubic foot per minute (cfm), 150 cfm, 4-8 mm respectively. First quantity of tablet 3kg were kept in pan at inlet temperature 60ºc till outlet temperature reaches to 45ºc. Then actual weight was determined. Then connect spray assembly tubing to peristaltic spray pump & this pump to filtered solution tanks. After than various parameter like spray rate,inlet air temperature, pan speed, distance of nozzle from tablet bed, spray width peristaltic pump RPM were adjusted. After completion of coating tablet were dried at inlet temperature of 85ºc by jogging of pan for 20min. Then tablet were unloaded from pan for evaluation

Optimization of atomizing air pressure: Coating was performed at different atomizing air pressure 0.5,1,1.5,2,2.5 kg/cm2 at constant spray rate 8ml/min, inlet air temperature 60ºC, pan speed 5 RPM, % solid content 8% & distance of nozzle from tablet bed (18cm) . Atomizing air pressure was optimized for CU, CPE & surface roughness.

At lower and higher atomizing air pressure unsatisfactory spray pattern was reported. At lower atomizing air pressure droplets formed of larger size due to this rough surface was observed. Hence CPE reported was not satisfactory at lower and higher atomizing air pressure. It was observed that at 1.5 kg/cm2 atomizing air pressure satisfactory CPE reported

Optimization of spray rate: Coating was performed at different spray rate of 4,6,8,10,12 ml/min at constant atomizing pressure(1.5 kg/cm2), inlet air temperature (60ºC), pan speed (5RPM), % solid content ( 8%) & distance of nozzle from tablet bed (18cm) and spray rate was optimized for CU,CPE & surface roughness.

It was observed that At lower spray rate solution was evaporated before reaching to tablet surface and at higher spray rate white spot, sticking & picking observed. It was reported that at lower and higher spray rate CPE was lower. Hence it was concluded that at 8 ml/min has to be used for coating process for further study

Optimization of distance between tablet bed and spray gun: Coating was performed at different distance between tablet bed and spray gun of 12,14,16,20 & 22 centimeter(cm) at constant atomizing air pressure(1.5 kg/cm2 ), inlet air temperature 60ºC , pan speed (5 RPM), % solid content (8%) and spray rate 8ml/min. Distance was optimized for CPE,CU & surface roughness.

At minimum distance white spot & rough surface was observed because solution was sprayed at high speed over tablet. On other hand at maximum distance unsatisfactory coating observed because solution get evaporated before reaching tablet surface. Hence coating CPE was lower at minimum & maximum distance. At 16cm distance coating was excellent.

Optimization of inlet air temperature: Coating was performed at different inlet air temperature 40,50,60,70 & 80ºC at constant % solid content (8%), atomizing air pressure(1.5 kg/cm2 ), spray rate (8ml/min), distance of nozzle from tablet bed (18cm)& speed of pan (5RPM) and inlet air temperature was optimized for CPE, CU & surface roughness.

At lower temperature sticking, picking and tablet get stick to pan. At high temperature solution get evaporated before reaching over tablet surface & nozzle block observed. Hence CU, CPE and surface roughness was noted at low and high temperature. But at 60ºC all parameter was found excellent and it was recommended that this temperature should be used for further study.

Optimization of pan differential pressure (DP): Coating was performed at different pan D P (with respect to coating area) 2,3,4,5 & 6 mm (D P was adjusted by changing inlet airCFM) at constant spray rate (8ml/min), inlet air temperature (60ºC ), pan speed (5RPM), atomization air pressure (1.5 kg/cm2), % solid content (8%) & distance of nozzle from tablet bed (16cm) and pan differential pressure was optimized for CU, CPE & surface roughness.

At lower pan DP undercoat, overcoat and sticking was recorded and at high DP spray pattern was disturbed because spray pattern was moving upward direction so white spot and undercoat tablets was observed. Hence CU, CPE & surface roughness was found unsatisfactory. But at 5mm DP spray pattern was observed satisfactory.

Optimization of pan speed (RPM): Coating was performed at different pan speed of 3,4,5,6 & 7 RPM at constant spray rate (8ml/min), inlet air temperature (60ºC ), atomization air pressure (1.5 kg/cm2), % solid content (8%) & distance of nozzle from tablet bed (16cm) & pan DP 5mm and pan speed was optimized for CU, CPE & surface roughness.

At minimum speed sticking, picking was recorded and as speed of pan increased theCU,CPE and surface roughness was found satisfactory because tablet mixing and distribution was done properly but at 5 RPM pan speed CU, CPE and surface roughness observed effective. Hence for further study 5RPM was used for investigation.

Optimization of % solid content: Coating was performed at different % solid content of 6, 8 & 10 at constant spray rate (8ml/min), inlet air temperature (60ºC ), atomization air pressure (1.5 kg/cm2), speed of pan (5RPM), distance of nozzle from tablet bed (16cm) & pan DP 5mm and % solid content was optimized for CU, CPE & surface roughness.

At lower % solid content particle get dried before reaching tablet surface hence CU, CPE and surface roughness was recorded good but as % solid content increased larger droplet was formed with non-uniform distribution of solution over tablets. But at 8% solid content CU, CPE and surface roughness was excellent.

Summary of the study was that At lower spray rate un-uniform coating was reported and at high rate white spot, sticking and picking problem was recorded. Variation in atomization air pressure affect over quality of coating process because at high atomization air pressure small droplet was formed and at low atomization air pressure big droplet was formed. Asdistance between tablet bed and spray gun increased disturbed spray spray pattern was observed even at minimum distance sticking & white spot over tablet noted. At low inlet air temperature rough surface, sticking, picking & white spot was observed and at high temperature white spot & rough surface observed. 

As pan DP reduced spray was disturbed. Higher RPM of pan increase the mixing and distributions of spray over the tablet. At high % solid content create problem like roughness over tablet. Hence optimized parameter which was recommended for further study as spray rate (8ml/min), atomization air pressure (1.5kg/cm2), distance of nozzle from tablet bed (16cm), inlet air temperature (60ºC), pan differential pressure (5mm), pan speed (5RPM) and % solid content(8%) .

Optimization of aqueous sustained release film coating parameters: Aqueous coating technology remains the main option for film coating of oral solid dosage forms. This is irrespective of the purpose of the film-coating applications, i.e. for conventional and modified-release film coatings.Aqueous coatingsystems are widely used for conventional film-coating systems (immediate release), enteric film-coating systems (delayed release), and barrier membrane controlled release film-coating systems (extended release).

PARAMETERS FOR DRUG TO BE FORMULATED IN SUSTAINED RELEASE DOSAGE FORM:

There are some physicochemical parameters for the drug selection to be formulated in sustained release dosage form which mainly includes the knowledge on the absorption mechanism of the drug form the Gastro Intestinal (G.I.) tract, its general absorbability, the drug’s molecular weight, solubility at different pH and apparent partition coefficient as shown in Table:

Table: Physicochemical parameters for drug selection

Parameter	Preferred value
Molecular weight/size	< 1000 Daltons
Solubility	> 0.1 mg/ml for pH 1 to pH 7.8
Apparent partition coefficient	High
Absorption mechanism	Diffusion
General absorbability	From all GI segments
Release	Should not be influenced by pH and enzymes

FACTORS AFFECTING THE ORAL SUSTAIN RELEASE DOSAGE FORM DESIGN:

A)   Pharmacokinetics and pharmacodynamics factor:

1. Biological half-life:

Drug with biological half-life of 2-8 hours are considered suitable candidate for sustain release dosage form, since this can reduce dosing frequency. However this is limited in that drugs with very short biological half lives may require excessive large amounts of drug in each dosage unit to maintain sustained effects, forcing the dosage form itself to become limitingly large.

2. Absorption:

Rate of absorption of a sustained formulating depends upon release rate constant of the drug from the dosage form, and for the drugs that are absorbed by active transport the absorption is limited to intestine.

3. Distribution:

The distribution of drugs into tissues can be important factor in the overall drug elimination kinetics. Since it not only lowers the concentration of circulating drug but it also can be rate limiting in its equilibrium with blood and extra vascular tissue, consequently apparent volume of distribution assumes different values depending n the time course of drug disposition. Thus for design of sustain release products, one must have information of disposition of drug.

4. Metabolism:

The metabolic conversion to a drug is to be considered before converting into another form. Since as long as the location, rate, and extent of metabolism are known a successful sustain release product can be developed

B) Drug properties relevant to sustain release formulation:

1. Dose size:

A dose size of 500-1000mg is considered maximal for a conventional dosage form. This also holds true for sustain release dosage forms. Since dose size consideration serves to be a parameter for the safety involved in administration of large amounts with narrow therapeutic range.

2. Ionization, pka and aqueous solubility:

Most drugs are weak acids or bases and in order for a drug to get absorbed, it must dissolve in the aqueous phase surrounding the site of administration and then partition into the absorbing membrane.

3. Partition coefficient:

Bioavailability of a drug is largely influenced by the partition coefficient, as the biological membrane is lipophilic in nature transport of drug across the membrane largely depends upon the partition coefficient of the drug. Drugs having low partition coefficient are considered as poor candidate for the sustain release formulation as it will be localized in the aqueous phase eg: Barbituric acid and vice a versa.

4. Drug stability:

When drugs are orally administered, they come across acid-base hydrolysis and enzymatic degradation. In this case, if the drug is unstable in stomach, drug release system which provides medication over extended period of time is preferred, whereas in contrast the drug unstable in intestine will face problem of less bioavailability.

Conclusion:

In recent decades, coating of pharmaceutical dosage forms has been subject of remarkable developmental efforts aiming to ensure and enhance end product quality. Improvements regarding particle movement, heat and energy transfer, film distribution, drying efficiency and continuous processing have contributed to significantly develop this technology.

REFERENCES:

1. J. K. Patel*, A. M. Shah and N. R. Sheth, Aqueous-based Film coating of Tablets: Study the Effect of Critical Process

Parameters, International Journal of PharmTech Research, Vol.1, No.2, April- June 2009, pp 235-240.

2. B.G. Prajapati, G.N. Patel, H.K. Solanki, Formulation and stastical Optimization of time controlled pulsatile release Propranolol Hydrochloride compressed coated tablet, Journal of Science & Technology. pp. 9-19.

3. Amitava Roya*, Amitava Ghosha, Supriya Datta, Effects of plasticizers and surfactants on the film forming properties of hydroxypropyl methylcellulose for the coating of diclofenac sodium tablets, Saudi Pharmaceutical Journal (2009) 17,

pp. 233–241.

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5. www.ijprd.com

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Data accumulated & compiled by:

Dewan Pavel (M. PHARM)

       Mundipharma (Bangladesh) Pvt. Ltd.

       Officer, Quality Assura