For many decades treatment of an acute disease or a chronic illness has been mostly accomplished by delivery of drugs to patients using various pharmaceutical dosage forms, including tablets, capsules, pills, suppositories, creams, ointments, liquids, aerosols and injectables as drug carriers. The design of oral sustained drug delivery system is subject to several inter-callated variables of considerable importance. Among these are the type of delivery system, the disease being treated, the patient, the length of therapy, a Pharmaceutical products designed for oral delivery and currently available in market are mostly the immediate-release type, which are designed for immediate release of drug for rapid absorption. 1,,2 All the pharmaceutical products formulated for systemic delivery via the oral route of administration, irrespective of mode of delivery (immediate, sustained or controlled release) and the design of dosage form (solid, dispersion or liquid) must be developed within intrinsic characteristic of gastrointestinal (GI) physiology.3,4

ADVANTAGES OF CONTROLLED RELEASE DOSAGE FORMS

1. Patient compliance due to reduction in the frequency of dosing.
2. Employ minimum drug.
3. Minimize or eliminates local and systemic side effects.
4. Obtain less protentiation or deduction in drug activity with chronic use.
5. Minimize drug accumulation with chronic dosing.
6. Improves efficacy in treatment.

DISADVANTAGES OF CONTROLLED RELEASE DOSAGE FORMS

1. They are costly.
2. Unpredictable and often poor in-vitro in-vivo correlations, dose dumping, reduced potential for dosage adjustment and increased potential first pass clearance.
3. Poor systemic availability in general.
4. Effective drug release period is influenced and limited by GI residence time.

RATIONALE OF CONTROLLED DRUG DELIVERY

The basic rationale for extended drug delivery is to alter the pharmacokinetic and pharmacodynamics of pharmacologically active moieties by using novel drug delivery systems or by modifying the molecular structure and/or physiological parameters inherent in a selected route of administration.5,6 It is desirable that the duration of drug action become more to design properly.7 Rate controlled dosage form, and less, or not at all, a property of the drug molecules inherent kinetic properties.8 As mentioned earlier, primary objectives of extended drug delivery are to ensure safety and to improve efficiency of drugs as well as patient compliance. This can be achieved by better control of plasma drug levels and frequent dosing. For conventional dosage forms, only the dose (D) and dosing interval (C) can vary and, for each drug, there exists a therapeutic window of plasma concentration, below which therapeutic effect is insufficient, and above which toxic side effects are elicited. This is often defined as the ratio of median lethal dose (LD 50) to median effective dose (ED50) 9, 10

MATERIALS AND EQUIPMENTS

CHEMICALS

EQUIPMENTS

EXPERIMENTAL WORK

PREFORMULATION STUDIES-

Organoleptic character

All the organoleptic character of paroxetine Hydrochloride was studied and it was found that all the character complies with IP standards.

 Bulk density and Tapped density

The density of Paroxetine Hydrochloride was found 0.206 g/ml .Tapped density was found 0.466g/ml. The results are shown in table 15.

Carr’s index

The measurement of free flowing powder can also be done by Carr’s index. The Carr’s index for all the formulations was found to be 55.682%, which reveals that the powder has poor  flow character.  The results are shown in table 15.

Angle of repose

The angle of repose for Paroxetine Hydrochloride was done as per the procedure. There was no proper flow through the funnel, indicates that powder has poor flow property. The results are shown in table 1.

PARTICLE SIZE

The Particle size was determined using mechanical sieve shaker as per the procedure. since 95% of the drug is retained on sieve # 50, the particle size of the drug lies between #50 and #18 i.e. 300 um an 1.00 mm. The results are shown in the table 2

The solubility of Paroxetine Hcl was carried out in different buffers as per the procedure and the results are show in the table 3 and figure 1.

Table 3: Solubility of Paroxitine Hcl in different pH conditions

PHYSICAL STABILITY OF THE ADMIXTURE

The drugs along with the excipients were kept under conditions specified and the results are given in table 4.

Table 4 : Drug – Excipient stability profile

There was no physical change observed in the admixture after one month at 60 ºC

Drug Excipient Compatibility Studies

FTIR analysis was conducted for the structure characterization and drug excipient Compatibility to which Paroxetine Hydrochloride showed the following character. All the FTIR characterization of drug excipient was analyzed and results showed that there was no shift of peak that correspond to pure drug as shown in fig 12.

 Calibration curves

Table 5: Standard plot of Paroxetine Hydrochloride in 0.1 N HCl

Figure 4: Standard plot of Paroxetine Hydrochloride in 0.1 N HCl

Table 6: Standard plot of Paroxetine Hydrochloride in phosphate buffer

Figure 5: Standard plot of Paroxetine Hydrochloride in phosphate buffer

ENTERIC COATING:

Coating solution preparation:

20% w/w of ACRYL-EZE.in water was prepared with continuous stirring for 1hr. It contains Methacrylic acid copolymer type C, Sodium carbonate, talc, silica, SLS and triethyl citrate. The final solution was passed through 100#. pH of the solution = 5.3

Enteric Coating for formulations F8, F9, F10, F11:

Coating solution was prepared using 400gm of Acryl white 20% w/w in water . Coating parameters:

Pan rpm = 35rpm

Pump rpm = 01

Pan size = 6”

Inlet temperature = 60 oC

CHARACTERIZATION OF PAROXETINE HYDROCHLORIDE MATRIX TABLETS (POST COMPRESSION PARAMETERS)

The tablets of different formulations of Paroxetine Hydrochloride were subjected to various evaluation tests, such as hardness, thickness weight variation, friability and drug content. All the result is shown in Table 20.

Thickness

The thickness of the tablets was found out using Vernier Caliper and the thickness found to be in the range of 4.02-4.12mm for the uncoated tablets (F1-F6). For the enteric coated tablets the thickness ranged from 4.21-4.30.Thus all formulations showed uniform thickness.

Hardness test

The hardness of tablet was measured by Monsanto hardness tester. Ten tablets from the batch were used for hardness studies and results showed they were in between 6.1-8.0 Kg/cm2. This is appropriate for matrix tablet.

Weight variation test

In a weight variation, the pharmacopoeial limit for the percentage deviation for tablets of more than 250 mg is ±5%. The average percentage deviation of all tablet formulations was found to be within the above limit, and hence all formulations passed the test for uniformity of weight as per official requirements.

Friability test

The Friability of all the formulation was below 1% as per IP specification. Drug content analysis/ Paroxetine Hydrochloride matrix tablet was tested for their drug content and all the formulation showed drug content more than 95%. All the tablet formulations showed acceptable pharmacotechnical properties and complied with the in-house specifications for weight variation, drug content, hardness, and friability. 

Table 12: Characterization of Paroxetine Hydrochloride matrix tablets

In vitro dissolution studies

COMPARISION OF FORMULATIONS WITH MARKETED FORMULATION PAXIL CR USING SIMILARITY FACTOR (F2):

The similarity factor (f2) was calculated for all the formulations as per the procedure and the values are shown in the table 30.

The similarity factor of all the formulation ranged from 30-70. The f2 value of formulation F10 was higher when compared to other formulations therefore F10 formulation was found to be similar to that of the marketed formulation (PAXIL CR).

       
           
       
    Figure 7: Stability dissolution profile of formulation (F6) at 25ºc/ 60% RH