QUALITY RISK MANAGEMENT IN SUSTAINED RELEASE TABLET FORMULATION DEVELOPMENT

Sajan MaharjanM.Pharm (1st year)

a dose for suitable time period is incorporated into one tablet from which the drug is slowly released.

helps to prevent peak of high plasma concentration and trough of low plasma concentration.

avoid side effects associated with high conc. and lack of activity associated to low conc. , giving better overall

therapy.

Sustained Release Tablets

Oral sustained release systems

Among all of the above, matrix systems are mostly used

Monolithic

Matrix

Reservoir

Proposed formula: Composition (in mg)Ingredients F1(1:1.25) F2(1:1.5) F3(1:1.75)

1. Diltiazem HCl (Active) 90 9090

2. Rosin (Polymer) 112.5 135 157.53. Talc 6 6 64. Magnesium Stearate 4 4 4

Formulation of sustained release tablet of Diltiazem HCl using Rosin as a matrix system

Tablet Compression

• Drug (Diltiazem Hydrochloride), polymer, magnesium stearate and talc were passed through sieve no. 80 separately and then mixed properly.

• The matrix tablets of the above formulations were compressed in a tablet compression machine.

Drug-excipient interaction studies (Preformulation studies)

• Differential Scanning Calorimetry (DSC), Fourier Transform Infrared (FTIR) Spectroscopy studies and HPTLC were used for the evaluation of physicochemical compatibility and interactions.

• helps in the prediction of interaction of the drug with polymers, diluents and lubricants used in tablet formulations

Evaluation of tablet formulations

• Evaluation of characteristics of powder blend (bulk density, tapped density, angle of repose, particle size) and tablets (hardness, friability, uniformity of weight and drug content).

• Drug content of formulated tablets (by using a UV spectrophotometer)

• Release studies (dissolution) performed at 75 rpm in 900 ml of phosphate buffer pH 7.4 at 37 ± 0.2 C.

Data analysis

Results and Risk identification

• DSC, FTIR and HPTLC results revealed that there is no interaction between the drug and the excipients used in the formulation

• The pre compression parameters like bulk density and compressibility index reveal that the powder mixture had good flow properties

• All the tablets were found to pass the uniformity of weight.• Content of Diltiazem HCl was found in the range of 98.5 to

101.0%.

200 400 600 800 10000

20

40

60

80

100

120

1:1.251:1.51:1.75

Time (min)

Perc

enta

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• 98.0% release was observed in 10 h for the ratio of 1:1.25,• 98.0% release was observed in 13 h for 1:1.5 and • 98.0% release was observed in 16 h for 1:1.75 • Performance of sustained release formulation was reported to be

greatly affected by physicochemical properties of polymer

• Dissolution

RISK ANALYSIS AND EVALUATION

• The polymer influences the drug release• release of drug was retarded due to the hydrophobic

nature of the polymer, which prevents the penetration of the dissolution medium into the matrix tablets leading to slower dissolution and diffusion of the drug molecules from the matrix system.

Risk Control

• formulation subjected to check the effect of release enhancers like lactose, MCC, and Mannitol

Composition (in mg)Ingredients F4(1:1.75) F5(1:1.75) F6(1:1.75)

1. Diltiazem HCl (Active) 90 9090

2. Rosin (Polymer) 157.5 157.5 157.53. Lactose 37.5 - -

4. MCC - 37.5 -5. Mannitol - - 37.5

6. Talc 9 9 97. Magnesium Stearate 6 6 6

• The composition was subjected to in vitro release studies• From the release profile the tablets containing MCC as diluent showed significant

increase in the release of drug, this might be due to swelling behavior of MCC in water and eventually disintegration of the tablets

Tablets contain mannitol and lactose as diluent showed significant higher drug release when compared with MCC. These might be due the rapid solubility of lactose and mannitol, tendency to form pores in the matrix which allow the dissolution medium to penetrate the matrix and dissolve the drug

Risk Control ( Contd…)

Risk Review and Risk Communication

•The polymer influences to slower dissolution and diffusion of the drug molecules from the matrix system •Release of drug from the matrices can be adjusted by using release enhancers like Lactose, Mannitol, MCC•These risks are communicated to production department and quality management department•The final formula is then submitted to production department:

Ingredients Composition (in mg)1. Diltiazem HCl 902. Rosin 157.53. Lactose 37.54. Talc 95. Magnesium Stearate 6

Tablet Wt. = 300 mg

Risks during manufacture and

distribution

• Adequate stability• Uniformity in

composition• Dose variation

• Cross contamination• Preservation

• Proper packaging• selection of packing

material• label control

Risk management throughout the life cycle of

product i.e from design development, mfg,

distribution with good quality assurance

procedure

Develop highest quality in the shortest time

THANK YOU