zolpidem tartrate -...

Zolpidem Tartrate 8.1 Rational behind selection of Drug

8.2 Need for Study

8.3 Methodology

8.4 Results & Discussion

8.5 Conclusion

8.6 Bibliography

Chapter 8 Zolpidem Tartrate - Rational

Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 224

8.1 RATIONAL BEHIND SELECTION OF ZOLPIDEM TARTRATE:

Insomnia is a sleep disorder characterized by the inability to sleep and/or to remain asleep

for a reasonable period during the night. Sufferers typically complain of being unable to

close their eyes or ‘rest their mind’ for more than a few minutes at a time. Insomnia has

significant direct and indirect effects on the health and wellness of affected individuals.

Zolpidem Tartrate, a non-benzodiazepine agent, is one of the most frequently prescribed

hypnotic drugs. Zolpidem was proven as effective as benzodiazepine in the management

of short-term insomnia. 1 The biological half-life of Zolpidem tartrate is 2.9 hours.

2

Zolpidem is a rapidly acting and also a rapidly eliminated hypnotic agent. As a result,

Zolpidem typically starts acting within 15-30 minutes, or less, after ingestion of the tablet

and its action can typically last for approximately 3 hours. This duration of action can be

considered too short in some circumstances. Lengthening the duration of action would

thus be desirable. Controlled release delivery systems for oral dosing are effective in

achieving optimal therapy with drugs that have a narrow therapeutic range of blood

concentration which eliminate rapidly. 3

Zolpidem is effective in reducing the time to sleep onset and increasing total sleep time.

The hypnotic effects of Zolpidem have been reported primarily in the first 3 hours post-

dose which can lead to sub therapeutic effects on sleep maintenance in the later portion of

the night for some patients. In an effort to expand the coverage of sleep complaints and

overcome the lack of efficacy in sleep maintenance, controlled drug delivery of Zolpidem

Tartrate is essential. Thus matrix formulation of Zolpidem Tartrate was the best

alternative for biphasic release. 4

Chapter 8 Zolpidem Tartrate – Need for study


8.2 NEED FOR THE STUDY:

An oral controlled release system which releases drug at zero-order rate is often

considered an ideal system for maintaining constant drug levels in plasma. This is based

on the assumption that drug absorption occurs rapidly and uniformly through the entire

GI tract, so that the rate of elimination dictates the rate at which the drug must release

from the dosage form. However, it is difficult to achieve, especially for once-daily dosage

forms, partly because the environment for drug diffusion and/or absorption varies along

the gastrointestinal (GI) tract. Normally, drug absorption is slow in the stomach and the

large intestine and fast in the small intestine; liquid volume becomes smaller while

viscosity of the GI content increases towards the distal segment of the GI tract. As a

result, a constant plasma concentration may not be obtainable even though a dosage form

with a zero-order in vitro release is administered. Thus, a release system with variable

rate of release may indeed be more desirable than a constant zero-order release system.

It is conceivable that when a single constant rate for drug release does not entirely satisfy

the therapeutic objective, the biphasic delivery system may be an interesting alternative.

Biphasic delivery (i.e. quick-slow or slow-quick) release profiles can generally be

obtained through incorporating a range of immediate-release, delayed release and

controlled-release formulation approaches.

Thus in an effort to expand the coverage of sleep complaints, overcome the lack of

efficacy in sleep maintenance, and to reduce the time to sleep onset biphasic release of

Zolpidem Tartrate is necessary. In the present research, an attempt has been made to

formulate Matrix tablets for biphasic release system of Zolpidem Tartrate. Biphasic

release system is used primarily when maximum relief needs to be achieved quickly, and

it is followed by a controlled release phase to avoid repeated administration. Matrix

devices, due to their chemical inertness, drug embedding ability and drug release

character, have gained steady popularity for controlling the release of a drug. 5

Thus, Biphasic release pattern of drug can be achieved by various approaches as single

layer monolithic matrix tablets, 6 bilayer matrix tablets,

7, 8 compression coated matrix

tablets 9, 10

and minitablets. 11, 12, 13

The matrix tablets can be designed to mimic initial

dosing while the controlled release of drug maintains a plasma concentration for a longer

duration of time.

Chapter 8 Zolpidem Tartrate - Methodology


8.3 METHODOLOGY FOR ZOLPIDEM TARTRATE

8.3.1 PREFORMULATION STUDIES:

Standardization and calibration curve of Zolpidem Tartrate had been performed as

explained in section 5.3.1.1 to 5.3.1.4. The concentration range selected for ZT was 2- 20

μg/ml in 0.01N HCl (pH 2) for calibration curve.

DRUG - POLYMER COMPATIBILITY study was done by FTIR and DSC studies.

8.3.2 FORMULATION OF BIPHASIC DRUG DELIVERY SYSTEM FOR

ZOLPIDEM TARTRATE:

Biphasic drug delivery system contains two different release phases as immediate

releasing phase and controlled releasing phase. Biphasic delivery systems are designed to

release a drug at two different rates or in two different periods of time: they are either

quick/slow or slow/quick. A quick/slow release system provides an initial burst of drug

release followed by a constant rate (ideally) of release over a defined period of time.

On the basis of these considerations, a CR biphasic drug delivery system is designed, in

the form of a double-component tablet, in which the one portion is formulated to obtain a

prompt release of the drug, with the aim of reaching a high serum concentration in a short

period of time. The second portion is a CR hydrophilic matrix, which is designed to

maintain an effective plasma level for a prolonged period of time.

Thus biphasic release system of ZT is formulated in the form of matrix tablets as:

1. Single layer monolithic matrix tablets by wet granulation

2. Bilayer matrix tablets by direct compression

3. Compression Coated matrix tablets by direct compression.

Dose calculation according to half life:

Dose for CR tablet of Zolpidem Tartrate is 12.5mg. Immediate release (IR) dose was

calculated using following formula and available pharmacokinetics data. Half life of

Zolpidem Tartrate reported in literature ranges from 1.4 to 4.5 h. Thus, loading dose was

calculated using different half-lives.

Dt = Dose (1 + 0.693 × t/t1/2)

Where Dt = Total dose; Dose = Immediate release dose; t = Total time period for which

controlled release is required and t1/2 = Half-life of drug.



Table 8.1: Dose Calculation According to Half- Life

Time

(for 6 hrs)

Half- life

1.5hr 2.85hr (Average) 4.5hr

Loading dose 2.799mg 5.085mg 6.496mg

Maintenance dose 9.701mg 7.415mg 6.004mg

Total dose 12.5mg 12.5mg 12.5mg

In the preparation of biphasic tablet, fraction of drug in both the phases was adjusted to

match marketed formulations drug release profile and as per USP requirement for initial

drug release of 50-60%.

Preliminary trials were conducted for different loading dose and maintenance dose ratios

to achieve desired drug release profile and it was concluded that instead of change in

loading dose of drug, drug release is mostly dependent on concentration of

superdisintegrant in IR phase and concentration of rate controlling polymer in CR

phase. Also preliminary trials were taken for selection of superdisintegrant for the IR

phase. Different disintegration accelerators (DA) were utilized to prepare the proper IR

phase using various super-disintegrants as croscarmellose sodium (CCS), crospovidone

(CP) and sodium starch glycolate (SSG). Direct compression technique was adopted for

the preparation of IR tablets. From cumulative % drug released, formulations containing

CCS was considered to be better than those containing CP and SSG.

Thus, finally dose in both IR and CR phases was adjusted to 50% of the total dose i.e.

6.25 mg in immediate and 6.25 mg in CR phase and CCS is selected as superdisintegrant

for IR phase.

8.3.2.1 FORMULATION OF SINGLE LAYER MONOLITHIC MATRIX

TABLETS FOR BIPHASIC RELEASE BY WET GRANULATION:

Single layer monolithic matrix tablets were prepared by wet granulation method. In this

method two different types of granules were prepared; one for IR and another for CR. For

preparation of IR granules, superdisintegrant Croscarmellose sodium and for preparation

of CR granules, different hydrophilic polymers like HPMC K100M CR, HPMC K200M,

Carbopol 71G, Polycarbophil and Guar gum were taken.

The preparation of single layer monolithic matrix tablets of ZT involved the following

steps:

I. Preparation of immediate release granules



II. Preparation of controlled release granules

III. Mixing of immediate and controlled release granules

IV. Compression of single layer monolithic matrix tablet

I. Preparation of immediate release granules for the matrix:

Drug and all the excipients were passed through sieve no. 40 and mixed properly. The

powder mix was granulated with purified water. The wet mass was passed through sieve

no. 16 and the granules were dried at 50°C for half an hour. The dried granules were

passed through sieve no. 20 and these granules were lubricated with a Magnesium

Stearate for 5 min. The lubricated granules were ready for compression.

II. Preparation of controlled release granules for the matrix:

Controlled release granules for the matrix were prepared by two methods as wet

granulation method using purified water as granulating fluid for both grades of HPMC

and Guar gum; and dry granulation by slug formation method was used for Carbopol

71G and Polycarbophil polymers. The drug, polymer, Avicel PH 101 and tartaric acid

were mixed well and granulated. The resulting wet mass was passed through sieve no. 16

and the granules were dried at 50°C for half an hour. The dried granules and granules

prepared by slug formation were passed through sieve no. 20. Obtained granules were

lubricated with a Magnesium Stearate for 5 min. and kept ready for compression.

III. Mixing of immediate and controlled release granules:

Both immediate and controlled release granules were mixed according to the composition

given in Table 8.2. Mixed granules were evaluated for precompression parameters.

IV. Compression of single layer monolithic matrix tablet for biphasic release:

Initially the volume of the die cavity (8 mm round, flat and plain) was adjusted equivalent

to the weight of single layer monolithic matrix tablet (130 mg). Then preweighed and

properly mixed both IR and CR granules were taken and placed in die cavity and

compressed with a proper compression force in order to obtain 4-5 Kg/cm2 hardness

using 8 mm punch on 10 stations tablet punching machine (Rimek mini press-1 Karnavati

Engineering Ltd, Mehsana, Gujarat). The matrix tablets were evaluated for

postcompression parameters.



8.3.2.2 FORMULATION OF BILAYER MATRIX TABLET FOR BIPHASIC

RELEASE BY DIRECT COMPRESSION:

The preparation of bilayer matrix tablet for biphasic release involved the following steps:

I. Preparation of immediate release layer

II. Preparation of controlled release layer

III. Compression of bilayer matrix tablet for biphasic release

I. Preparation of the immediate release layer:

The IR ingredients were accurately weighed and added into the blender in ascending

order. The powder mix was blended for 10 min to obtain uniform distribution of the drug

in formulation and was evaluated for precompression parameters.

II. Preparation of the controlled release layer:

CR layer ingredients were accurately weighed and added into the blender in ascending

order. The powder mix was blended for 10 min to obtain uniform distribution of the drug

in formulation and was evaluated for precompression parameters.

III. Compression of bilayer matrix tablet for biphasic release:

In the present study bilayer tablet was prepared manually using 10 stations tablet

punching machine. Accurately weighed amount of CR powder mix according to different

formulations (Table 8.3) was fed manually into die cavity. CR layer was compressed at

mild compression force. After that IR powder mix was accurately weighed and manually

fed into the die on CR layer and compressed at a predetermined compression pressure of

5-6 Kg/cm2 using 8 mm flat punches. The matrix tablets were evaluated for


8.3.2.3 FORMULATION OF COMPRESSION COATED MATRIX TABLET

FOR BIPHASIC RELEASE BY DIRECT COMPRESSION

For the preparation of compression coated matrix tablets (CCMT) direct compression

method was used. Core tablets were prepared for CR using different hydrophilic polymers

as HPMC K100M CR, HPMC K200M, Carbopol 71G, Carbopol 971P, Polycarbophil and

Guar gum. These core tablets were coated with IR layer containing CCS.

The preparation of CCMTs for biphasic release involved the following steps:

I. Preparation of immediate release layer

II. Preparation of core tablets for controlled release layer

III. Compression of compression coated matrix tablet for biphasic release



I. Formulation of the immediate release layer:

The IR ingredients were accurately weighed and added into the blender in ascending

order. The powder mix was blended for 10 min to obtain uniform distribution of the

drug in formulation and was evaluated for precompression parameters.

II. Formulation of Core tablets for controlled release:

Ingredients of core tablets for controlled release were accurately weighed and added

into the blender in ascending order. The powder mix was blended for 10 min to obtain

uniform distribution of the drug in formulation. The powder blend was evaluated for

precompression parameters. The core tablets, weighing 120 mg, were prepared by

direct compression with flat-tip punches and dies with a 6-mm diameter. The core

tablets were evaluated for postcompression parameters.

III. Compression of compression coated matrix tablet for biphasic release:

For the preparation of the biphasic release delivery system by compression coating,

the die of the tabletting machine was filled manually with the weighed amounts of the

IR component and the core tablet (Table 8.4) prior to compression. Half of the fast

releasing powder was put into the die to make a powder bed, on the centre of which a

core tablet was placed. Then the other half of the powder was added to cover the core

tablet. The formulations differed in the type and concentration of polymers used in the

preparation of the core tablet. Compressed core tablet systems were prepared by direct

compression, with flat-tip punches and dies with a 9.45 mm diameter at compression

force of 5-6 Kg/cm2. The compression coated matrix tablets were evaluated for


8.3.3 EVALUATION OF MATRIX TABLETS OF ZOLPIDEM TARTRATE:

8.3.3.1 PRE COMPRESSION PARAMETERS:

Evaluations of powder blend or granules:

The powder blends of IR and CR layers in bilayer and compression coated tablets and

granule mixture of both layers in single layer monolithic matrix tablets were evaluated for

precompression parameters as angle of repose, bulk and tapped density, Carr’s index and

Hausner’s ratio as described in section 5.3.3.1.



Table 8.2: Composition of Single Layer Monolithic Matrix Tablets of Zolpidem Tartrate

Formulation Code SF1 SF2 SF3 SF4 SF5 SF6 SF7 SF8 SF9 SF10 SF11 SF12

IMMEDIATE RELEASE PHASE

Zolpidem Tartrate 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25

CCS 20 20 20 20 20 20 20 20 20 20 30 20

Avicel PH 101 16.75 16.75 16.75 16.75 16.75 16.75 16.75 16.75 16.75 16.75 6.75 16.75

HPMC K4M 5 5 5 5 5 5 5 5 5 5 5 5

Magnesium Stearate 2 2 2 2 2 2 2 2 2 2 2 2

Total weight 50 50 50 50 50 50 50 50 50 50 50 50

CONTROLLED RELEASE PHASE

Zolpidem Tartrate 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25

HPMC K100M 40 50 - - - - - - - - - -

HPMC K200M - - 50 40 30 - - - - - - -

Carbopol 71G - - - - - 50 40 - - - - -

Polycarbophil - - - - - - - 50 40 - - -

Guar gum - - - - - - - - - 50 50 40

Avicel PH 101 21.75 11.75 11.75 21.75 31.75 11.75 21.75 11.75 21.75 11.75 11.75 21.75

Tartaric acid 10 10 10 10 10 10 10 10 10 10 10 10

Magnesium Stearate 2 2 2 2 2 2 2 2 2 2 2 2

Total weight 80 80 80 80 80 80 80 80 80 80 80 80

*All ingredients expressed in mg



Table 8.3: Composition of Bilayer Matrix Tablets for Biphasic Release of Zolpidem Tartrate Formulation code BF1 BF2 BF3 BF4 BF5 BF6 BF7 BF8 BF9 BF10 BF11 BF12 BF13 BF14 BF15


Zolpidem Tartrate 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25

CCS 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40

Avicel PH 102 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20

Ludiflash 3.75 3.75 3.75 3.75 3.75 3.75 3.75 3.75 3.75 3.75 3.75 3.75 3.75 3.75 3.75

Total weight 70 70 70 70 70 70 70 70 70 70 70 70 70 70 70

CONTROLLED RELEASE PHASE

Zolpidem Tartrate 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25

HPMC K100M 10 20 - - - - - - - - - - -

HPMC K200M - - 20 10 - - - - - - - - -

Carbopol 71G - - - - 20 20 15 10 - - - - -

Polycarbophil - - - - - - - - 20 10 - - -

Carbopol 971P - - - - - - - - - - 10 20

Guar gum 10 20 30

Ludiflash 51.75 41.75 41.75 51.75 41.75 36.75 41.75 41.75 41.75 41.75 51.75 41.75 51.75 41.75 31.75

Tartaric acid 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10

CCS 20 20 20 20 20 25 20 20 20 20 20 20 20 20 20

Magnesium

Stearate

2 2 2 2 2 2 2 2 2 2 2 2 2 2 2

Total weight 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100

*All ingredients expressed in mg



Table 8.4: Composition of Compression coated matrix tablets for Biphasic Release of Zolpidem Tartrate Formulation code CCF1 CCF2 CCF3 CCF4 CCF5 CCF6 CCF7 CCF8 CCF9 CCF10 CCF11 CCF12 CCF13 CCF14 CCF15


Zolpidem tartrate 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25

CCS 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40

Avicel PH 102 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80

Ludiflash 73.75 73.75 73.75 73.75 73.75 73.75 73.75 73.75 73.75 73.75 73.75 73.75 73.75 73.75 73.75

Total weight 200 200 200 200 200 200 200 200 200 200 200 200 200 200 200

CONTROLLED RELEASE PHASE (CORE TABLET)

Zolpidem tartrate 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25 6.25

HPMC K100M 10 20 - - - - - - - - - - - - -

HPMC K200M - - 20 10 - - - - - - - - - - -

Carbopol 71G - - - - 20 20 15 10 - - - - - - -

Polycarbophil - - - - - - - - 10 20 - - - - -

Carbopol 971P - - - - - - - - - - 10 20 - - -

Guar gum - - - - - - - - - - - - 10 20 30

Ludiflash 71.75 61.75 61.75 71.75 61.75 56.75 61.75 66.75 61.75 71.75 71.75 61.75 71.75 61.75 51.75

Tartaric acid 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10

CCS 20 20 20 20 20 25 25 25 20 20 20 20 20 20 20

Magnesium Stearate 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2

Total weight 120 120 120 120 120 120 120 120 120 120 120 120 120 120 120 *All ingredients expressed in mg



8.3.3.2 POST COMPRESSION PARAMETERS:

Matrix Tablets and also core tablets prepared for compression coating were evaluated for

parameters like weight variation, thickness, hardness and friability as described in section

5.3.3.2.

Drug content uniformity:

It was determined by weighing 5 tablets individually, and the drug was extracted in buffer

pH 2 (0.01N HCl). The solution was filtered through 0.45 µm membrane filter and the

absorbance was measured at 294 nm after suitable dilution and calculated the

concentration of the drug.

In-vitro dissolution:

The in-vitro dissolution studies were performed as per USP specifications using the USP-

II (Paddle) dissolution apparatus at 100 rpm. 14

Electrolab TDT-08L USP dissolution test apparatus

Apparatus used USP type 1 dissolution test apparatus

Dissolution medium 0.01N HCl

Dissolution medium volume 500 ml

Temperature 37 ± 0.5ºC

Speed of paddle in rpm 100 rpm

Sampling intervals 30 min for first 2 h and then 1 h up to 6 hours

Sample withdrawn volume 5 mL

Absorption measurement 294 nm Method:

A sample (5 mL) of the solution was withdrawn from the dissolution apparatus

at predetermined time intervals and the samples were replaced with fresh dissolution

medium maintained at the same temperature. Drug content in withdrawn sample was

determined by UV/Visible Spectrophotometer (UV-1800) at 294 nm. The study was

performed in triplicate.

8.3.4 MATHEMATICAL MODELLING:

The release profile of the drug obtained was analysed using different kinetic models such

as zero order, first order, Higuchi, Hixson Crowell and Korsmeyer – Peppas model in

order to evaluate the release mechanism from matrices.

8.3.5 COMPARISON OF DISSOLUTION PROFILES:

Difference factor f1 and similarity factor f2 were calculated for all the formulations by

comparing drug release profile of all formulations with marketed formulation of



Zolpidem tartrate as STILNOCT® 12.5 mg was used as a marketed bilayer tablet

(SANOFI-SYNTHELAB) as a reference product. Both factors were calculated as

described in section 5.3.5.

8.3.6 STABILITY STUDY:

Stability studies were carried out at 40°C / 75% RH for the optimized formulations for

three months. After 30, 60 and 90 days storage period the formulations were evaluated for

drug content in 0.01N HCl (pH 2) buffer.

Chapter 8 Zolpidem Tartrate – Results & Discussion


8.4 RESULTS AND DISCUSSION FOR ZOLPIDEM TARTRATE

8.4.1 PREFORMULATION STUDIES: The results of preformulation studies carried out in this study are presented below.

8.4.1.1 Identification of pure drug:

Identification of Zolpidem Tartrate was carried out by Infra-Red Absorption

Spectrophotometry and FTIR spectrum of pure drug is shown in Figure 8.1 FTIR

spectrum (Table 8.5) of pure drug was studied and characteristic absorption peaks

obtained for C=C; -CH3; C=C; =C-H; C=O; C=N etc. groups were found to be confirmed

the drug.

Table 8.5: FTIR characteristic peaks of Zolpidem Tartrate

Sr.

no.

Functional groups Characteristic peaks (nm) Observed peaks(nm)

Stretching Bending Stretching Bending

1 -CH3 3000 - 2840 1340 - 1375 2920.18 - 2868 1344

2 C=C 2900- 2950 1400 - 1470 2924 1456

3 =C-H 3050 - 3010 900 - 690 3053.42 895

4 -C=O 1680 - 1630 1635

5 -O-H of Tartrate 3348

6 =C-N 1400 - 1000 1396

7 C=N- N Tertiary amine 1690 - 1640 1635

Figure 8.1: FTIR Spectrum of Zolpidem Tartrate

8.4.1.2 Melting Point Determination

Melting point of Zolpidem Tartrate was found to be 195°C - 197

°C indicating purity of the

drug sample.

8.4.1.3 Solubility Studies:

Solubility of Zolpidem Tartrate was determined in pH 1.2 (0.1 N HCl), pH 2 (0.01N

HCl), and pH 4.5 acetate buffer, different pH 6.8, pH 7.2, pH 7.4, pH 7.8 phosphate



buffers and water. Solubility of Zolpidem Tartrate decreased as pH increased and it was

maximum in 0.01N HCl as shown in Table 8.6

Table 8.6: Saturation Solubility of Zolpidem Tartrate in different pH

Sr. no. pH Concentration (mg/ml)

1 1.2 87.64

2 2 88.22

3 4.5 22.61

4 6.8 0.265

5 7.2 0.161

6 7.4 0.148

7 7.8 0.159

8 Distilled Water 12.54

8.4.1.4 Analytical method estimation:

The ultraviolet spectrophotometric method was used to analyse Zolpidem Tartrate.

UV Spectrum of Zolpidem Tartrate in 0.01N HCl (pH 2) buffer: UV spectrum of Zolpidem Tartrate in 0.01N HCl (pH 2) buffer showed the maximum

absorption wavelength at 294 nm (λma ) (Figure 8.2)

Figure 8.2: UV Spectrum of Zolpidem Tartrate in 0.01N HCl

Figure 8.3: Standard calibration curve for Zolpidem Tartrate in 0.01N HCl



Standard Calibration Curve of Zolpidem Tartrate in 0.01N HCl:

The calibration curve was found to be linear in the concentration range of 2-20 µg/ml in

0.01N HCl at its λmax, 294 nm (Figure 8.3). The coefficient of correlation (R2) was found

to be R2 = 0.9998 with slope of 0.0431.

8.4.1.5 Compatibility Studies

Compatibility of drug and polymers were confirmed by FTIR and DSC studies.

8.4.1.5.1 FTIR Studies

FTIR techniques have been used here to study the physical and chemical interaction

between drug and polymers used.

Figure 8.4: IR Spectra of Zolpidem Tartrate with various Polymers

In the present study, it has been observed that there were no major shifts in Zolpidem

Tartrates vibrational frequencies in FTIR spectra of mixture of drug and polymers,

indicating no chemical interaction. Hence it can be concluded that there is compatibility

between ZT and the polymers used in formulations. (Figure 8.4)

8.4.1.5.2 DSC Studies:

The thermograms are generated for pure drug and drug-polymer mixture using DSC-60,

Shimadzu, Japan. (Figure 8.5-8.7) The DSC thermogram of ZT shows one sharp

endothermic peak at 194.72°C. The peak is associated with the melting of Zolpidem

Tartrate (reported m.p is 193°C - 197°C).



Figure 8.5: DSC thermograms of Drug with various Polymers

In all drug-polymer blends, the melting endotherm of ZT was well preserved with little

change in terms of shape and positioning of peak. These minor changes in the melting

endotherm of the drug may be attributed to mixing with excipients. The mixing may

lower the purity of each component in the mixture, and result in slight shift in melting

points. Slight variations in the peak shape and melting point may be also triggered by

varying sample geometry during mixing. (Figure 8.5) The broad endothermic peak near

100°C was attributed to the evaporation of physically bound-water or absorbed water

from the carbopol polymers during heating. Hence, the changes in thermograms may not

truly representative of incompatibility.

8.4.2 PRE COMPRESSION PARAMETERS:

Lubricated IR granules and CR granules of Single layer Monolithic matrix tablets were

combined and mixture of granules was evaluated for different precompression parameters

and results are given in Table 8.7. Similarly, powder blend of IR & CR layers of both

Bilayer matrix tablets and Compression coated tablets were evaluated for precompression

parameters and results are given in Tablet 8.8 & 8.9.

Angle of repose of all the powder blends and granule mixtures ranged from 19.38 to

29.41 and the compressibility index less than 20 indicated good flow property and



compressibility. Carr‟s index is comparatively less than powder blend mixtures for

Bilayer and Compression Coated tablets ranged from 9.65 to 13.82 showed free flowing

property of granules. (Table 8.7) The Bulk and Tapped Density of the prepared powder

blends of different formulations ranged from 0.363 to 0.416 and 0.416 to 0.478

respectively. Hausner‟s ratio is less than 1.2 indicated again free flowing properties of

granules and powder blends.

Table 8.7: Precompression Parameters of IR and CR Granules Blend of Single

Layer Monolithic Matrix Tablets of Zolpidem Tartrate

Formulation Code

Angle of Repose(θ)

Bulk Density (g/ml)

Tapped Density (g/ml)

Carr’s Index. (%)

Hausner’s ratio

SF1 22.80 0.384 0.434 11.52 1.13

SF2 23.34 0.377 0.434 13.13 1.15

SF3 21.78 0.392 0.454 13.66 1.16

SF4 21.04 0.377 0.425 11.29 1.13

SF5 22.68 0.384 0.425 9.65 1.11

SF6 19.38 0.377 0.425 11.29 1.13

SF7 19.51 0.392 0.444 11.71 1.13

SF8 24.83 0.363 0.416 12.74 1.15

SF9 22.35 0.374 0.434 13.82 1.16

SF10 20.32 0.392 0.434 9.68 1.11

SF11 21.34 0.407 0.462 11.90 1.14

SF12 24.34 0.416 0.478 12.97 1.15 Table 8.8: Precompression Parameters of IR and CR Powder Blends of Bilayer

Matrix Tablets for Biphasic Release by Direct Compression

Formulation Code

Angle of Repose(θ)

Bulk Density (g/ml)

Tapped Density (g/ml)

Carr’s Index. (%)

Hausner’s ratio

IRPB* 22.80 0.382 0.432 11.57 1.13

BF1 27.34 0.351 0.402 12.69 1.15

BF2 27.78 0.416 0.496 16.13 1.19

BF3 28.04 0.372 0.414 10.14 1.11

BF4 26.68 0.413 0.484 14.67 1.17

BF5 29.74 0.401 0.473 15.22 1.18

BF6 27.51 0.376 0.422 10.90 1.12

BF7 27.83 0.389 0.467 16.70 1.20

BF8 27.35 0.367 0.432 15.05 1.18

BF9 23.20 0.387 0.466 16.95 1.20

BF10 29.68 0.375 0.434 13.59 1.16

BF11 28.53 0.397 0.478 16.95 1.20

BF12 25.00 0.387 0.431 10.21 1.11

BF13 22.01 0.383 0.462 17.10 1.21

BF14 20.90 0.412 0.49 15.92 1.19

BF15 24.89 0.399 0.478 16.53 1.20 *IRPB – Immediate Release Powder blend



Table 8.9: Precompression Parameters of IR and CR Powder Blends of

Compression Coated Matrix Tablet for Biphasic Release by Direct Compression

Formulation

Code

Angle of

Repose(θ)

Bulk Density

(g/ml)

Tapped

Density (g/ml)

Carr’s

Index. (%)

Hausner’s

ratio

IRPB* 21.37 0.466 0.532 12.41 1.14

CCF1 26.87 0.449 0.536 16.23 1.19

CCF2 20.23 0.478 0.570 16.14 1.19

CCF3 23.98 0.459 0.521 11.90 1.14

CCF4 24.24 0.479 0.564 15.07 1.18

CCF5 26.08 0.484 0.594 14.18 1.17

CCF6 26.35 0.472 0.528 10.61 1.12

CCF7 26.00 0.472 0.555 14.95 1.18

CCF8 25.91 0.502 0.591 15.06 1.18

CCF9 28.34 0.491 0.588 16.50 1.20

CCF10 22.37 0.492 0.587 16.18 1.19

CCF11 23.50 0.491 0.584 15.92 1.19

CCF12 26.08 0.469 0.564 18.62 1.20

CCF13 26.35 0.499 0.594 18.35 1.19

CCF14 26.00 0.467 0.528 11.55 1.13

CCF15 23.98 0.472 0.555 14.95 1.18

*IRPB – Immediate Release Powder Blend

8.4.3 POSTCOMPRESSION PARAMETERS

The Single Layer Monolithic matrix tablets, Bilayer and Compression coated Tablets with

different CR polymers for biphasic release of Zolpidem Tartrate using wet granulation

and direct compression method were subjected to various in vitro evaluation tests like

thickness, diameter, hardness, friability, uniformity of weight, drug content. The results of

post compression parameters for core tablets for compression coating and matrix tablets

by different formulation methods of Zolpidem Tartrate are depicted in Table 8.10 to 8.12.

Table 8.10: Post compression parameters of Single Layer Monolithic Matrix Tablets

of Zolpidem Tartrate for Biphasic Release by Wet Granulation

Formulation

code

Diameter

(mm)

Thickness

(mm)*

Hardness

(Kg/cm2)*

Weight

Variation(mg)*

Friability

(%)

Drug content

(%)*

SF1 8 3.27±0.01 4.40±0.34 130.15±0.93 0.195 99.24±0.57

SF2 8 3.26±0.01 4.10±0.45 130.45±0.94 0.098 98.89±0.49

SF3 8 3.27±0.01 4.70±0.25 130.30±1.03 0.293 100.23±0.29

SF4 8 3.21±0.01 4.85±0.24 129.90±0.78 0.255 101.26±0.28

SF5 8 3.27±0.02 4.15±0.33 130.10±0.85 0.081 99.27±0.03

SF6 8 3.22±0.01 4.85±0.24 129.25±0.91 0.098 102.85±0.64

SF7 8 3.27±0.01 4.20±0.34 128.15±0.93 0.195 101.68±0.28

SF8 8 3.26±0.01 4.40±0.45 131.45±0.94 0.098 100.29±0.18

SF9 8 3.27±0.01 4.70±0.25 130.30±1.03 0.293 98.49±0.18

SF10 8 3.26±0.01 4.30±0.34 131.15±0.93 0.195 100.24±0.35

SF11 8 3.24±0.01 4.60±0.45 129.45±0.94 0.098 99.89±0.27

SF12 8 3.28±0.01 4.75±0.25 130.30±1.03 0.263 99.23±1.02

* Values are represented as mean ± SD (n=10)



Table 8.11: Post compression parameters of Bilayer Matrix Tablets of Zolpidem

Tartrate for Biphasic Release by Direct Compression

Formulation

code

Diameter

(mm)

Thickness

(mm)*

Hardness

(Kg/cm2)*

Weight

Variation(mg)*

Friability

(%)

Drug content

(%)*

BF1 8 3.50±0.39 4.47±0.71 170.21±0.37 0.53 98.49±0.76

BF2 8 3.59±0.42 4.54±0.86 169.11±0.92 0.72 99.59±0.49

BF3 8 3.62±0.32 4.60±2.22 171.83±0.38 0.70 101.38±1.25

BF4 8 3.75±0.56 4.95±0.85 171.07±0.69 0.12 102.39±0.44

BF5 8 3.73±0.42 4.23±0.34 169.75±0.46 0.80 100.29±0.10

BF6 8 3.53±0.41 4.52±0.95 171.59±0.33 0.49 101.78±2.02

BF7 8 3.52±0.40 4.26±0.55 169.53±0.38 0.12 100.21±1.01

BF8 8 3.58±0.80 4.30±0.12 170.25±0.58 0.96 99.38±0.93

BF9 8 3.85±0.99 4.32±0.08 171.35±0.36 0.23 98.83±0.32

BF10 8 3.24±0.70 4.58±0.29 172.45±0.21 0.90 99.27±0.49

BF11 8 3.60±0.49 4.56±0.35 169.51±0.27 0.33 100.49±0.29

BF12 8 3.34±0.58 4.26±0.17 170.72±1.42 0.83 101.28±0.27

BF13 8 3.53±0.39 4.42±0.71 171.21±0.37 0.63 98.49±0.18

BF14 8 3.54±0.42 4.56±0.86 168.11±0.92 0.72 99.59±0.25

BF15 8 3.65±0.32 4.62±2.22 172.83±0.38 0.70 101.38±0.28


8.4.3.1 THICKNESS AND DIAMETER

The thickness of the 8 mm Single Layer Monolithic matrix tablets of ZT with different

rate retarding polymers was found in the range of 3.21±0.01 to 3.28±0.01 mm. (Table

8.10) The thickness of the Bilayer matrix tablets was found to be 3.24±0.70 to 3.75±0.56

mm. (Table 8.11) The thickness of the core tablets was 3.41±0.37 to 3.90±0.66 and for

CC matrix tablets was 6.41±0.37 to 6.92±0.66. The thickness of tablets was variable

depending on weight of the tablet and punch size. (Table 8.12)

8.4.3.2 HARDNESS

Hardness for all matrix tablet formulations was found to be between 4 to 5 Kg/cm2 (Table

8.10 to 8.12). Hardness of the core tablets for compression coating was found to be 4.54

to 5.51 Kg/cm2 which were slightly more than compression coated tablets.

8.4.3.3 FRIABILITY

The percentage friability of all formulations was found to be below 1% ensuring that all

the batches were mechanically stable. (Table 8.10 to 8.12)

8.4.3.4 WEIGHT VARIATION

Weight variation test shown for Single Layer Monolithic matrix tablets, CR cores for

compression coating and Bilayer and CC matrix tablets of ZT with different polymers as

130 ± 2 mg, 120 ± 2.5 mg, 170 ± 2 mg and 320 ± 2.5 mg variation respectively. This

ensures that it is within a limit according to IP specifications of 10% for 130 and 120 mg

tablets and of 7.5% for 170 and 320 mg matrix tablets. (Table 8.10 to 8.12)



Table 8.12: Post compression parameters of Core and Compression Coated Matrix Tablets of Zolpidem Tartrate for Biphasic Release

by Direct Compression Formulation Code Diameter

(mm) Thickness

(mm)* Hardness *

(Kg/cm2) Weight Variation

(mg)* Friability (%)

(n = 20) Drug content *

CRCT CCMT CRCT CCMT CRCT CCMT CRCT CCMT CRCT CCMT CRCT CCMT

CCF1 6 9.45 3.86±0.34 6.86±0.34 5.11±0.34 4.87±0.32 120.21±0.37 320.59±0.30 0.53 0.29 100.28±0.48 99.87±0.01

CCF2 6 9.45 3.90±0.66 6.90±0.66 5.34±0.45 4.68±0.57 119.11±0.92 321.43±0.27 0.72 0.37 101.83±0.58 99.90±0.03

CCF3 6 9.45 3.69±0.63 6.69±0.63 5.51±0.25 4.89±0.61 121.83±0.38 319.82±0.99 0.70 0.31 101.23±0.49 99.48±0.93

CCF4 6 9.45 3.83±0.81 6.83±0.81 5.00±0.24 4.36±0.39 121.07±0.69 321.45±0.34 0.12 0.63 100.28±0.29 98.37±0.14

CCF5 6 9.45 3.88±0.70 6.88±0.70 5.50±0.33 4.69±0.65 119.75±0.46 322.32±0.34 0.80 0.74 100.28±1.19 99.38±0.28

CCF6 6 9.45 3.66±0.49 6.66±0.49 5.47±0.24 4.98±0.65 121.59±0.33 319.55±0.35 0.49 0.38 100.84±0.28 98.48±1.01

CCF7 6 9.45 3.88±0.42 6.88±0.42 5.54±0.34 4.54±0.52 119.53±0.38 318.32±0.73 0.12 0.73 102.34±1.20 99.89±0.38

CCF8 6 9.45 3.58±0.44 6.58±0.44 5.39±0.45 4.62±0.71 120.25±0.58 319.41±0.20 0.96 0.72 100.45±0.29 98.28±0.28

CCF9 6 9.45 3.88±0.46 6.88±0.46 5.50±0.25 4.86±1.11 121.35±0.36 320.78±1.00 0.23 0.50 99.84±0.19 100.93±0.19

CCF10 6 9.45 3.41±0.37 6.41±0.37 5.00±0.39 4.99±0.60 122.45±0.21 321.09±0.45 0.53 0.45 98.98±0.17 102.27±0.57

CCF11 6 9.45 3.59±0.43 6.59±0.43 5.29±0.59 4.61±0.94 119.51±0.27 322.47±0.25 0.72 0.43 101.23±0.16 100.2±0.82

CCF12 6 9.45 3.88±0.70 6.92±0.66 4.69±0.65 4.49±0.61 122.32±0.34 320.82±0.99 0.74 0.36 100.28±2.10 98.48±0.37

CCF13 6 9.45 3.66±0.49 6.64±0.63 4.98±0.65 4.56±0.39 119.55±0.35 320.45±0.34 0.38 0.73 100.84±0.10 99.37±0.39

CCF14 6 9.45 3.88±0.42 6.85±0.81 4.54±0.52 4.79±0.65 118.32±0.73 321.32±0.34 0.73 0.84 99.89±0.93 101.28±0.02

CCF15 6 9.45 3.58±0.44 6.87±0.70 4.62±0.71 4.38±0.65 119.41±0.20 318.55±0.35 0.72 0.48 98.28±0.04 102.84±0.39

* Values are represented as mean ± SD (n=10); CRCT – Controlled Release Core Tablets; CCMT – Compression Coated Matrix Tablets



8.4.3.5 DRUG CONTENT UNIFORMITY

Good uniformity of drug content was found among different formulations of Monolithic,

Bilayer and Compression coated matrix tablets of Zolpidem Tartrate by wet granulation

for monolithic and direct compression for rest of formulations using different polymers

and the percentage drug content estimations showed values in the range of 98.28±0.48 to

102.85±0.03%. (Table 8.10 to 8.12)

8.4.3.6 IN VITRO DRUG RELEASE

The CR formulations of Zolpidem Tartrate has to treat sleep disorders by giving biphasic

release of drug at predetermined controlled rate to provide therapeutically effective

amount of the drug for at least about 6 hours. USP monograph for „Zolpidem Tartrate

Extended Release Tablets‟ had given tolerance limits for the percentage of dissolved drug

at the times specified should conform to Accepatance table as mentioned in Table 8.13.

Table 8.13: Acceptance Table for Zolpidem Tartrate dissolution as per USP:

Time (h) Time (min) Amount dissolved

0.5 30 50%–70%

1.5 90 70%–85%

4 240 NLT 85%

To ascertain the above fact, the in vitro drug release characteristics of all formulated

Zolpidem Tartrate matrix tablets was performed for six hours in 0.01N HCl.

The IR layer of the biphasic matrix tablets prepared by any method (Single layer

monolithic, Bilayer or Compression coating), contain CCS in IR granules or layer which

swells rapidly upto 4-8 times its original volume on contact with water. Thus, it performs

its disintegrating action by wicking through capillary action and fibrous structure

respectively with minimum gelling and liberated ZT for immediate action. Disintegration

of the IR layer did not have any effect on characteristics of CR layer.

As soon as the matrix tablet comes in contact with the dissolution media, IR layer

disintegrated with initial IR of drug within 30 min with simultaneous imbibition of

dissolution medium by the tablet with the formation of gel layer of polymer around the

tablet. The CR of ZT was found to be a function of the polymer concentration. The effect

of rate retarding polymers as HPMC K100M CR, HPMC K200M, Carbopol 71G,

Carbopol 971P, Polycarbophil and Natural gums as Guar gum on drug release was due to

swelling nature of polymer which causes subsequent thicker gel formation with decrease

in drug release.



Thus, it is clear from preliminary different trials and different formulation aspects that

biphasic release of the Zolpidem Tartrate from matrix tablets was mainly due to proper

proportion of CCS in IR layer and rate retarding polymer in the CR layer.

8.4.3.6.1 IN VITRO DRUG RELEASE OF SINGLE LAYER MONOLITHIC

MATRIX TABLETS OF ZOLPIDEM TARTRATE FOR BIPHASIC RELEASE

BY WET GRANULATION:

The biphasic release of Zolpidem Tartrate was found to be a function of the proper CCS

concentration for IR granules and rate retarding polymer concentration for CR layers. The

effect of polymers at different concentrations for different polymers on the release of drug

from tablet matrices was studied. Drug release from the matrix tablets was found to

decrease with increase in drug polymer ratio.

In this study, the effect of various polymers as different grades of HPMC as HPMC

K100M, HPMC K200M; Carbopol 71G and Polycarbophil; Gums as Guar Gum on the

release behaviour of Zolpidem Tartrate from matrix type tablets were evaluated and

results of in vitro release studies are shown in Table 8.14.

In vitro drug release studies from HPMC Matrices:

The viscosity grade of HPMC influences drug release profiles by modifying the diffusion

and erosion behavior of the matrix system. Figure 8.6 illustrates the in vitro release

profiles of Zolpidem Tartrate from the monolithic matrix tablets containing different

concentrations and viscosity grades of HPMC.

Figure 8.6: In vitro drug release profile of Zolpidem Tartrate Single Layer Monolithic

Matrix Tablets (SF1 to SF5) by Wet granulation with (40 and 50 mg) HPMC K100M CR

and (50, 40 and 30 mg) HPMC K200M It is clearly evident that all the matrix tablets prepared using HPMC K100M employed at

concentrations 40 mg in CR layer failed to control Zolpidem Tartrate release at 1.5 h

within 70 to 85%. Release of Zolpidem was slightly more. As the concentration of the

rate retarding polymer from CR layer was increased from 40 mg to 50 mg for formulation

0

20

40

60

80

100

120

0 1 2 3 4 5 6 7

% C

um

mu

lati

ve d

rug

rele

ase

Time (h)

STILNOCT

SF1

SF2

SF3

SF4

SF5



SF2, the release pattern was found to be controlled with initial burst release. This may be

due to less hardness of matrix tablets with 50 mg than 40 mg HPMC K100M. But after

half hour, it modulated the drug release due to the formation of continuous gel layer on

their surfaces.

On the other hand, matrix tablets containing 50 mg HPMC K200M (SF3) was able to

control Zolpidem tartrate release from the start depending on high viscosity of HPMC

used. Formulation SF4 and SF5 was designed with less amount of HPMC K200M i.e. 40

and 30 mg respectively to obtain initial rapid release of drug and found that formulation

SF5 with only 30 mg of HPMC K200M was sufficient to modify the release as USP

criteria.

Thus relative utility of less amount of high viscosity grade of HPMC, for example

K200M in formulating biphasic release showed predetermined release profile of

Zolpidem Tartrate.

In vitro drug release studies from Carbopol Matrices:

Figure 8.7 shows the comparative study of the release of Zolpidem Tartrate from

Carbopol 71G and Polycarbophil matrices. The in vitro dissolution profile from 50 mg

Carbopol 71G (SF6) matrices showed initial delay in drug release as compared to 40 mg

Carbopol 71G (SF7) matrices. Formulation SF7 with 40 mg of Carbopol 71G is effective

in achieving drug release profile as per USP criteria. Also this is the same with

formulation SF9 with 40 mg of Polycarbophil is sufficient than formulation SF8 with 50

mg of Polycarbophil. Formulations SF6 and SF8 with 50 mg of Carbopol 71G and Polycarbophil respectively

did not comply with the release requirements at 30th

and 90th

min as per USP

specifications and found 40 mg of respective polymers only is sufficient in CR layer.


Matrix Tablets (SF6 to SF9) by Wet granulation with (40 and 50 mg) Carbopol 71G and

Polycarbophil

0

20

40

60

80

100

120

0 1 2 3 4 5 6 7

% C

um

mu

lati

ve d

rug

rele

ase

Time (h)

STILNOCT

SF6

SF7

SF8

SF9



In vitro drug release studies from Guar Gum Matrices:

Natural gums are biodegradable and nontoxic, which hydrate and swell on contact with

aqueous media, and these have been used for the preparation of dosage form for biphasic

release. The in vitro drug release profile of monolithic matrix formulations of Zolpidem

Tartrate with 50 and 40 mg Guar gum and marketed formulation Stilnoct are shown in

Figure 8.8.


Matrix Tablets (SF10 to SF12) by Wet granulation with (50 and 40 mg) Guar gum The drug release from the matrix tablets was found to decrease with increase in gum

proportion. In formulations SF10 with 50 mg of Guar gum shown highly controlled drug

release and formulation SF12 with 40 mg of Guar gum shown initial rapid release till 1.5

h and both formulations did not comply with 30 and 90 min. dissolution criteria as per

USP.

Preliminary trials for Single layer Monolithic matrix tablets suggested that biphasic

release of the Zolpidem Tartrate from Single Layer matrix tablets was mainly due to

proper proportion rate retarding polymer in the CR layer. But formulation SF11 was tried

with 50 mg of Guar gum in CR layer and 30 mg of CCS in IR layer instead of 20 mg as in

all other formulations. The drug release profile from formulation SF11 shown biphasic

release of drug as required due to inclusion of more amount of CCS in IR layer indicated

initial burst release at 30 min and successive CR at 90 min with 79.12 ± 4.18% drug

release which is within the specifications of dissolution (Table 8.13). Formulation SF12

with 40 mg of Guar gum shown high erodability with rapid release till 1.5 h and

formulation SF10 with 50 mg of Guar gum shown high water uptake and high swelling

ability to control the drug release from the start but inclusion of 30 mg CCS solved both

the issues.

0

20

40

60

80

100

120

0 1 2 3 4 5 6 7

% C

um

mu

lati

ve d

rug

rele

ase

Time (h)

STILNOCT

SF10

SF11

SF12



For assessment and comparison with the release specifications as per USP, the % of drug

released from the prepared monolithic matrix tablets with polymers after 0.5, 1.5 and 4th

h

were extracted directly from the release data and were graphically depicted in Figures 8.9

and 8.10.

It was quite evident that formulations SF3, SF6, SF8, SF10 and SF12 did not match with

0.5 h and 1.5 h criteria of drug release within 50 to 70% and 70 to 85% respectively. But,

all the formulations followed 4th

h criteria of drug release not less than 85%.

Figure 8.9: The percentage of Zolpidem Tartrate released after 0.5, 1.5 and 4 hours

from HPMC K 100M, HPMC K200M and Guar Gum Single Layer Monolithic

matrix tablets.


from Carbopol 71G and Polycarbophil Single Layer Monolithic matrix tablets. Thus, the Single Layer Monolithic matrix tablets prepared with 30 mg of HPMC K200M

showed biphasic release as required than all other polymers. When dissolution profiles of

same grade but different concentration ranges were compared, a significant difference

(p<0.05) was observed. Formulations SF2, SF5, SF9 and SF11 showed no significant

difference with marketed formulation (P>0.05).

0

20

40

60

80

100

% C

um

ula

tive

Dru

g R

ele

ase

0.5 h

1.5 h

4 h

0

20

40

60

80

100

SF6 SF7 SF8 SF9 STILNOCT

% C

um

ula

tive

Dru

g R

ele

ase

0.5 h

1.5 h

4 h



Table 8.14: In Vitro Drug Release profile of Single Layer Monolithic Matrix Tablets of Zolpidem Tartrate by Wet Granulation

Time (h) SF1 SF2 SF3 SF4 SF5 SF6 SF7 SF8 SF9 SF10 SF11 SF12 STILNOCT

0.25 37.04

±1.96

50.01

±2.04

30.73

±0.64

41.12

±2.93

45.42

±0.35

38.25

±4.28

52.96

±0.84

36.28

±8.18

49.15

±4.07

29.38

±2.61

57.39

±2.95

66.13

±1.25

53.20

±2.47

0.5 56.23

±4.96

54.73

±2.17

38.70

±0.71

50.40

±1.75

58.59

±3.37

48.02

±0.40

62.28

±5.18

42.56

±7.61

53.89

±4.02

35.29

±1.74

64.24

±3.01

78.80

±2.84

59.68

±2.52

1 77.98

±8.75

64.64

±2.05

58.46

±2.11

63.15

±2.20

71.88

±2.02

55.08

±3.70

73.07

±3.08

52.01

±6.26

62.78

±3.13

56.59

±2.24

69.74

±2.29

84.74

±5.32

68.53

±1.95

1.5 85.70

±10.66

71.31

±2.14

64.63

±2.12

74.92

±0.53

81.04

±2.85

61.82

±1.96

79.18

±0.31

60.49

±6.56

70.57

±1.95

69.45

±1.84

79.12

±4.18

88.04

±3.45

75.00

±1.72

2 90.36

±11.13

79.11

±1.53

74.34

±2.50

84.27

±0.50

84.51

±4.29

67.90

±2.40

88.15

±1.83

67.89

±5.96

79.28

±1.93

78.61

±2.53

87.15

±4.29

91.54

±2.23

82.01

±1.93

3 96.34

±10.67

86.70

±1.84

79.65

±3.01

93.25

±0.46

89.07

±4.18

78.02

±2.47

95.21

±1.98

79.88

±6.03

87.49

±1.72

89.65

±2.14

93.47

±2.85

94.04

±4.83

90.90

±1.95

4 97.96

±8.72

93.87

±1.24

84.81

±4.42

97.01

±0.31

92.42

±3.29

87.03

±4.32

97.74

±1.69

89.36

±6.66

93.35

±1.95

95.83

±2.05

96.87

±2.92

95.19

±2.37

94.82

±3.13

5 98.15

±6.60

98.51

±1.74

90.73

±5.27

98.87

±0.60

97.76

±3.01

95.16

±5.60

98.82

±0.91

96.28

±6.46

98.91

±2.52

98.51

±2.17

99.05

±3.38

96.13

±4.58

98.59

±4.02

6 97.49

±5.12

99.88

±2.61

94.51

±4.79

99.87

±0.48

99.35

±2.95

100.78

±5.62

99.73

±1.19

100.66

±6.79

99.94

±2.47

99.87

±2.04

99.58

±0.34

96.52

±2.34

100.0

±4.07




Table 8.15: In Vitro Drug Release profile of Bilayer Matrix Tablets of Zolpidem Tartrate by Direct Compression

Time (h) BF1 BF2 BF3 BF4 BF5 BF6 BF7 BF8 BF9 BF10 BF11 BF12 BF13 BF14 BF15 STILNOCT

0.25 57.12

±0.34

47.23

±0.93

47.36

±1.39

56.76

±1.23

39.68

±0.35

50.81

±0.34

56.34

±0.36

56.57

±0.89

48.89

±0.98

56.21

±0.37

73.17

±0.97

60.90

±0.67

83.69

±9.36

74.77

±2.39

49.93

±0.93

53.20

±3.24

0.5 70.12

±0.32

58.99

±3.84

51.47

±4.95

59.66

±3.84

46.30

±0.98

55.09

±4.85

66.16

±0.45

74.20

±3.94

56.01

±3.94

64.93

±1.93

77.32

±1.83

63.19

±2.38

85.86

±2.38

80.42

±2.09

56.66

±0.83

59.68

±1.23

1 78.34

±3.64

69.26

±1.28

58.89

±6.74

68.92

±2.93

57.84

±0.25

60.38

±0.34

74.53

±0.94

81.09

±2.89

62.99

±2.93

72.47

±2.89

81.84

±1.92

70.22

±1.92

87.32

±0.92

85.71

±3.94

65.47

±0.79

68.53

±0.32

1.5 84.35

±1.83

72.56

±2.93

65.27

±2.09

75.88

±1.02

64.17

±2.45

66.40

±2.93

79.25

±0.87

88.20

±1.87

68.25

±0.34

78.81

±3.89

86.21

±0.37

75.55

±1.09

88.84

±0.93

89.63

±2.94

72.85

±0.47

75.00

±1.23

2 89.23

±2.94

76.87

±1.93

72.19

±1.03

81.92

±2.93

71.40

±1.98

73.73

±1.93

81.62

±1.38

93.56

±0.28

75.00

±0.45

86.63

±2.93

89.41

±0.78

80.07

±1.02

90.03

±1.29

92.24

±2.93

78.61

±0.84

82.01

±5.23

3 93.42

±3.94

86.99

±4.58

82.94

±0.37

89.33

±1.83

81.13

±0.34

84.45

±0.34

91.79

±9.84

96.93

±0.17

85.94

±0.27

93.15

±1.83

91.73

±0.98

87.39

±1.02

97.50

±2.90

96.05

±1.08

86.13

±0.32

90.90

±6.75

4 95.32

±1.98

93.68

±0.21

90.52

±0.83

93.49

±3.94

86.67

±0.94

91.87

±0.34

97.09

±1.98

98.35

±0.03

92.43

±3.45

96.55

±0.93

97.09

±2.93

94.20

±0.27

98.89

±2.03

97.50

±2.03

92.35

±0.93

94.82

±3.84

5 97.23

±0.32

96.48

±0.23

94.92

±0.73

96.91

±2.93

93.15

±0.54

96.14

±1.23

99.66

±3.94

99.42

±3.98

97.08

±0.17

98.89

±0.27

99.66

±2.93

97.50

±0.92

99.16

±1.09

98.89

±0.93

96.17

±0.58

98.59

±3.98

6 99.32

±2.84

98.74

±0.98

97.18

±2.04

99.33

±0.93

95.60

±1.23

99.04

±3.94

100.5

±0.94

100.0

±1.29

99.24

±0.72

99.59

±0.27

100.5

±0.28

99.00

±0.73

99.89

±1.23

99.16

±1.02

99.69

±0.93

100.0

±1.21




8.4.3.6.2 IN VITRO DRUG RELEASE OF BILAYER MATRIX TABLETS OF

ZOLPIDEM TARTRATE FOR BIPHASIC RELEASE BY DIRECT

COMPRESSION:

The preparation of tablets in the form of multi layers is used to provide systems for the

administration of drugs to provide CR tablet preparations by providing swelling layers.

Bilayer tablet is one of the approaches for biphasic release system. 15

Attempts have been

made for preparation of biphasic release with fixed concentration of superdisintegrant in

IR layer and variable concentrations of rate retarding polymers in CR layer for adjusting

release pattern according to marketed formulation and USP guidelines of Zolpidem

Tartrate Extended release tablet. In the bilayer tablet one of the layers was formulated

with superdisintegrant CCS for immediate drug release while another layer was

formulated with different hydrophilic polymers as HPMC K100M, HPMC K200M,

Carbopol 71G, Carbopol 971P, Polycarbophil and Guar gum for extended drug release.

From preliminary trials, formulations for Bilayer matrix tablets required comparatively

more amount of CCS, a superdisintegrant in IR layer and fewer amounts of rate retarding

polymers in CR layer. The release profile of drug from bilayer matrix tablets is given in

Table 8.15 and depicted in Figures 8.11 to 8.14.

The release of Zolpidem was found to be a function of the polymer concentration

(ranging from 10 to 30 mg) in CR layer.

Also the assessment and comparison of different matrices with the release specifications

as per USP; the percent of drug released from the prepared bilayer matrix tablets with

different polymers after 0.5, 1.5 and 4th

h were extracted directly from the release data

and were graphically depicted in Figure 8.15 and 8.16.

Figure 8.11: In vitro drug release profile of Zolpidem Tartrate Bilayer Matrix Tablets (BF1

to BF4) by Direct Compression with (10 and 20 mg) HPMC K100M CR and (20, 10 mg)

HPMC K200M

0

20

40

60

80

100

120

0 1 2 3 4 5 6 7

% C

um

mu

lati

ve d

rug

rele

ase

Time(h)

STILNOCT

BF1

BF2

BF3

BF4



It was observed that formulation BF1 with 10 mg of HPMC K100M was not sufficient to

control the drug release at 30th

min. But formulation BF4 with 10 mg of HPMC K200M

sufficiently controlled the drug release at all-time points as per USP and match with

marketed formulation‟s release profile. To elicit biphasic release of ZT 20 mg of HPMC

K100M (BF2) is necessary whereas 20 mg of HPMC K200M retarded the drug release

also at 90 min.(Figure 8.11 and 8.15)

The effect of amount of Carbopol 71G is significant for directly compressed Bilayer

matrix tablets. As the concentration of the rate retarding polymer from CR layer was

decreased from 20 mg to 15 mg for formulations BF5 to BF7 respectively, the release

pattern was found to be improved with initial burst release (Figure 8.12). Formulation

BF8 containing 10 mg of Carbopol 71G is not sufficient to give biphasic release of drug

as required. In formulation BF6, inclusion of more amount of CCS with 20 mg of

Carbopol 71G also is not giving initial rapid release at 30 and 90 min. It was clearly

indicated that drug release is dependent only on polymer concentration in rate retarding

CR layer. Formulation BF7 containing 15 mg of Carbopol 71G showed release pattern

identical to the marketed product. (Figure 8.12 and 8.16)

Formulation BF10 and BF11 with 10 mg of Polycarbophil and Carbopol 971P; BF13

and BF14 with 10 and 20 mg of Guar gum respectively showed rapid initial release and

was unable to retard the drug release. So it was concluded that to control the drug release

up to 6 h with initial burst release 20 mg of Polycarbophil and Carbopol 971P and 30 mg

of Guar gum was necessary. Directly compressed guar gum matrices shown rapid erosion

with less amount of polymer. (Figures 8.13 to 8.16)


to BF8) by Direct Compression with (20, 15 and 10 mg) Carbopol 71G

0

20

40

60

80

100

120

0 1 2 3 4 5 6 7

% C

um

mu

lati

ve d

ru

g r

ele

ase

Time(h)

STILNOCT

BF5

BF6

BF7

BF8




to BF12) by Direct Compression with (20 and 10 mg) Polycarbophil and Carbopol 971P


to BF15) by Direct Compression with (10, 20 and 30 mg) Guar Gum

Figure 8.15: The percentage of Zolpidem Tartrate released after 0.5, 1.5 and 4 h

from HPMC K 100M, HPMC K200M and Guar Gum Bilayer matrix tablets.

Figure 8.16: The percentage of Zolpidem Tartrate released after 0.5, 1.5 and 4 h

from Carbopol 71G, Polycarbophil and Carbopol 971P Bilayer matrix tablets.

0

20

40

60

80

100

120

0 1 2 3 4 5 6 7

% C

um

mu

lati

ve d

rug

rele

ase

Time(h)

STILNOCT

BF9

BF10

BF11

BF12

0

20

40

60

80

100

120

0 1 2 3 4 5 6 7

% C

um

mu

lati

ve d

rug

rele

ase

Time(h)

STILNOCT

BF13

BF14

BF15

0

20

40

60

80

100

% C

um

ula

tive

Dru

g R

ele

ase

0.5 h

1.5 h

4 h

0

20

40

60

80

100

% C

um

ula

tive

Dru

g R

ele

ase

0.5 h

1.5 h

4 h



When dissolution profiles of same grade but different concentration ranges were

compared, a significant difference (p<0.05) was observed. Formulations BF2, BF4, BF9

and BF15 showed no significant difference with marketed formulation (P>0.05). Thus, the

release of ZT was found to be a function of the polymer concentration. The bilayer tablets

rapidly disintegrated giving initial rapid release due to the presence of CCS in IR layer

which swells very quickly in the dissolution fluid. All formulations retarded the release of

drug for 6 h. Disintegration of the IR layer did not have any effect on characteristics of the CR

layer. It was confirmed that 10mg of HPMC K200M.exhibited biphasic release profile of drug as

per USP criteria and marketed formulations release pattern.

8.4.3.6.3 IN VITRO DRUG RELEASE OF COMPRESSION COATED MATRIX

TABLETS OF ZOLPIDEM TARTRATE FOR BIPHASIC RELEASE BY DIRECT

COMPRESSION:

A compression coated tablet made of a CR tableted core and an IR tableted coat was

prepared by direct compression. Both the core and the coat contained a model drug as

Zolpidem Tartrate. The CR effect was achieved with different rate retarding polymers as

HPMC K100M, HPMC K200M, Carbopol 71G, Carbopol 971P, Polycarbophil and Guar

gum to modulate the release of the drug. The in vitro drug release profile from these

tablets showed the desired biphasic release behaviour: the ZT contained in the fast

releasing component was dissolved within 30 minutes, whereas the drug in the core tablet

was released at controlled rate depending on the composition of the matrix tablet.

The composition of the fast component provided a hard and rapidly disintegrating tablet

at low compression forces, and the compaction of the core tablet was not affected the

structure or the release behavior of these units. Upon evaluation of the crushing strength,

visual inspection of the fractured surfaces of the compression coated system revealed that

the appearance of the core tablet in the compact system was similar. Figure 8.17 to 8.20

shows the release profiles of Zolpidem Tartrate from the biphasic DDSs. Figure 8.21 and

8.22 shows comparison of different matrices with the release specifications as per USP.

These compression coated tablet systems upon contact with the dissolution media, the

coated IR layer of tablets rapidly disintegrated. The prompt tablet disintegration was due

to the presence of CCS which swells very quickly when in contact with water. After the

initial phase, the release was dependent on the composition of the matrix core, in

particular, the type and concentration of the polymer in CR layer.



Table 8.16: In Vitro Drug Release profile of Compression Coated Matrix Tablets of Zolpidem Tartrate by Direct Compression Time(h) CCF1 CCF2 CCF3 CCF4 CCF5 CCF6 CCF7 CCF8 CCF9 CCF10 CCF11 CCF12 CCF13 CCF14 CCF15 STILNOCT

0.25 69.91

±1.23

51.78

±1.23

43.72

±0.29

51.65

±1.29

41.13

±0.93

44.98

±1.29

51.55

±3.48

53.84

±2.38

51.79

±3.84

45.92

±3.94

47.66

±2.38

43.62

±1.23

71.94

±0.89

67.96

±2.45

60.02

±2.38

53.20

±3.24

0.5 73.03

±1.48

56.17

±0.92

48.32

±0.89

56.41

±1.29

45.28

±0.38

54.35

±0.38

58.92

±0.94

64.84

±4.85

59.15

±2.83

50.73

±2.99

64.15

±0.92

61.27

±3.47

77.86

±3.94

77.26

±0.78

65.66

±0.94

59.68

±1.23

1 76.97

±3.94

63.24

±0.83

57.46

±1.92

67.11

±0.38

55.21

±1.93

60.03

±9.34

65.91

±3.84

78.88

±6.12

65.72

±3.84

58.30

±0.38

69.91

±2.83

71.86

±0.36

85.18

±2.89

86.16

±3.49

72.21

±0.78

68.53

±0.32

1.5 88.14

±2.09

69.88

±0.38

61.08

±0.39

76.04

±0.48

62.85

±2.98

69.19

±0.48

70.46

±0.38

87.41

±0.38

72.17

±1.28

65.84

±3.94

73.03

±1.82

83.44

±0.84

95.81

±0.67

91.07

±2.93

77.27

±4.56

75.00

±1.23

2 94.59

±0.93

75.49

±1.98

66.88

±0.38

83.53

±3.49

69.72

±3.84

74.31

±0.94

77.21

±2.93

91.10

±0.83

80.51

±3.94

71.86

±3.91

76.97

±3.84

91.45

±0.98

97.72

±2.48

93.84

±1.28

82.23

±4.56

82.01

±5.23

3 97.34

±1.23

84.89

±0.27

75.91

±0.27

92.43

±4.95

79.65

±0.38

84.95

±3.94

86.78

±2.93

97.01

±3.48

89.33

±2.89

85.59

±0.93

88.14

±0.93

94.99

±2.34

98.74

±0.89

97.20

±3.24

85.93

±3.46

90.90

±6.75

4 99.11

±0.34

92.31

±0.28

83.87

±1.92

96.47

±0.48

84.07

±0.93

91.79

±5.97

91.20

±0.74

98.49

±0.98

93.82

±3.89

92.88

±2.38

94.59

±9.45

96.75

±4.57

99.32

±3.48

98.49

±3.56

91.57

±0.57

94.82

±3.84

5 99.89

±0.84

99.61

±0.98

90.91

±0.27

98.60

±4.93

88.90

±3.94

96.97

±5.69

97.48

±0.89

99.26

±0.48

98.17

±2.98

96.38

±0.37

97.34

s±0.93

97.26

±6.43

99.56

±0.48

99.46

±3.89

95.84

±3.48

98.59

±3.98

6 99.99

±1.02

100.0

±1.92

95.60

±1.92

99.85

±2.93

93.24

±0.98

99.83

±0.48

99.30

±0.47

99.86

±0.48

99.30

±0.47

98.33

±0.92

99.11

±2.45

99.34

±2.38

99.98

±2.18

99.93

±0.89

99.23

±0.38

100.0

±1.21




Figure 8.17: In vitro drug release profile of Zolpidem Tartrate Compression Coated Matrix

Tablets (CCF1 to CCF4) by Direct Compression with (10 and 20 mg) HPMC K100M CR

and (20, 10 mg) HPMC K200M


Tablets (CCF6 to CCF8) by Direct Compression with (20, 15 and 10 mg) Carbopol 71G


Tablets (CCF9 to CCF12) by Direct Compression with (20 and 10 mg) Polycarbophil and

Carbopol 971P


Tablets (CCF13 to CCF15) by Direct Compression with (10, 20 and 30 mg Guar Gum

0

20

40

60

80

100

120

0 1 2 3 4 5 6 7

% C

um

mu

lati

ve d

rug

rele

ase

Time (h)

STILNOCT

CCF1

CCF2

CCF3

CCF4

0

20

40

60

80

100

120

0 1 2 3 4 5 6 7

% C

um

mu

lati

ve d

rug

rele

ase

Time (h)

STILNOCT

CCF5

CCF6

CCF7

CCF8

0

20

40

60

80

100

120

0 1 2 3 4 5 6 7

% C

um

mu

lati

ve d

rug

rele

ase

Time (h)

STILNOCT

CCF9

CCF10

CCF11

CCF12

0

20

40

60

80

100

120

0 1 2 3 4 5 6 7

Cu

mm

ula

tive

% d

rug

rele

ase

Time (h)

STILNOCT

CCF13

CCF14

CCF15



The ability of the rate retarding polymers to hydrate and form a gel layer around a core is

well known and is essential to sustaining and controlling the release of a drug from a

matrix.16

When dissolution profiles of same grade but different concentration ranges were

compared, a significant difference (p<0.05) was observed. Formulations CCF4, CCF7 and

CCF9 showed no significant difference with marketed formulation (P>0.05).


from HPMC K 100M, HPMC K200M and Guar Gum Compression Coated matrix

tablets.


from Carbopol 71G, Polycarbophil and Carbopol 971P Compression Coated matrix

tablets. All the formulations, upon contact with the dissolution media, rapidly disintegrated into

the immediate-releasing phase and released 40 – 70% of the drug within 15 min. The

formulations except CCF1, CCF13 and CCF14 contain 10 mg of HPMC K100M and 10

and 20 mg of Guar gum respectively shown more than 70% of the drug released within 30

min. Formulations CCF3 and CCF5 containing 20 mg of HPMC K200M and Carbopol

71G respectively shown more controlled drug release at all-time points which is less than

0102030405060708090

100

% C

um

ula

tive

Dru

g R

ele

ase

0.5 h

1.5 h

4 h

0

20

40

60

80

100

% C

um

ula

tive

Dru

g R

ele

ase

0.5 h

1.5 h

4 h



range given as per USP Criteria. Formulations CCF6 containing 20 mg of Carbopol 71G

and 25 mg of CCS in CR core matrix and formulation CCF10 containing 20 mg of

Polycarbophil not complied with release profile at 90 min which is less than 70%. 10, 20

mg of Guar gum in core matrix is not sufficient to extend and control the drug release till

4 h.

Thus the results obtained with the dissolution showed that the biphasic release profile is

dependent on both the type and amount of polymer in the core tablet. It was found that

formulation CCF4 containing only 10 mg of HPMC K200M was sufficiently given

biphasic release as per USP criteria and match to marketed formulations release profile

perfectly.

8.4.4 KINETIC ANALYSIS OF DRUG RELEASE

The results for the fitting of the kinetics model for drug release from monolithic, bilayer

and compression coated matrix tablets are shown in Table 8.17 to 8.19 respectively. The

values for the release rate constants (K0, K1, KH, KKP), the correlation coefficients (R2),

and the release exponent (n) are considered. The correlation coefficient (R2) was used as

an indication of the best fit, for each of the models considered. Some release mechanisms

can be better elucidated indirectly, either by comparing the fitting of the models of

relaxational polymer and matrix erosion and of pure diffusion or by the exponent n.

8.4.4.1 SINGLE LAYER MONOLITHIC MATRIX TABLETS OF ZOLPIDEM

TARTRATE BY WET GRANULATION:

The drug release data from single layer monolithic matrix tablets of Zolpidem Tartrate

with different polymers were fitted to various Kinetic models to know the release

mechanism. Table 8.17 shows the best-fit release kinetic data with the highest values of

regression coefficient (R2).

The kinetic data showed that the release of drug from majority of the formulations

followed First order and Korsemeyer Peppas model indicating drug release is purely by

diffusion and also diffusion coupled with erosion. Formulations SF1, SF3, SF4, SF8, SF9

and SF11 followed first order kinetics. The best fit kinetics for the formulations SF2, SF5,

SF7 and SF12 is Korsemeyer Peppas indicating diffusion coupled with erosion. Only

formulations SF6 and SF10 followed Higuchi kinetics indicating drug release is by

Fickian diffusion.

The value of n is 0.117 to 0.396 indicating Quasi Fickian diffusion mechanism.



8.4.4.2 BILAYER MATRIX TABLETS OF ZOLPIDEM TARTRATE BY DIRECT

COMPRESSION:

Data analysis of release profiles according to different kinetic models shown in above

Tables 8.18. For formulations BF1, BF2, BF5, BF7, BF10 and BF14, the model that best

fit the data was Korsemeyer Peppas. Formulations BF4, BF8 and BF12 followed first

order kinetics indicating drug release dependent on the concentration of drug remained to

be released. Rest all the formulations as BF3, BF6, BF9, BF11, BF13 and BF15 best fits

to Higuchi matrix model indicating Fickian diffusion. The value of n is very less i.e.

0.061 to 0.291 indicating Quasi Fickian diffusion of drug.

8.4.4.3 COMPRESSION COATED MATRIX TABLETS OF ZOLPIDEM

TARTRATE BY DIRECT COMPRESSION

For the compressed core tablet system, the model that best fit the data for CCF1, CCF4,

CCF5, CCF8, CCF11, CCF12, CCF13 and CCF14 was first order. Rest all the

formulations except CCF15 followed Higuchi kinetics. Formulation CCF15 showed

Korsemeyer Peppas as best fit model. The value of n is 0.117 to 0.364 indicating Quasi

Fickian diffusion as the release mechanism.

From all the three types of formulations for biphasic release of Zolpidem tartrate shown

value of n is less than 0.45 indicating Quasi-Fickian diffusion. It can be achieved when

drug diffusion is rapid compared to the constant rate of solvent-induced relaxation and

swelling in the polymer.

Therefore, the release of drug from the prepared matrix tablets is controlled by the

diffusion and swelling of the polymer followed by drug diffusion through the swelled

polymer and slow erosion of the tablet. Three processes of water penetration,

gelatinization and diffusion rate have the rate limiting steps for the release of drug from

majority of formulations prepared by any method as Single layer, Bilayer or CC matrices,

with first order or Korsemeyer Peppas release kinetics.



Table 8.17: Kinetic Data Derived from Various Kinetic Models for Single Layer Monolithic matrix tablets of Zolpidem Tartrate for

Biphasic Release

Formulation

Code

Zero order First order Higuchi Korsemeyer Peppas f1 f2

Best Fit

Model K0 R2 K1 R

2 KH R

2 KKP R

2 n

SF1 57.02 0.664 1.728 0.949 -4.947 0.817 1.269 0.894 0.315 8.26 53.11 FIRST

SF2 55.13 0.916 2.014 0.892 -10.38 0.985 1.404 0.990 0.234 3.67 69.41 KMP

SF3 40.13 0.846 1.832 0.977 -3.502 0.947 1.07 0.973 0.396 14.69 42.89 FIRST

SF4 49.81 0.850 1.907 0.997 -5.452 0.951 1.253 0.985 0.310 4.72 61.22 FIRST

SF5 57.43 0.792 1.742 0.959 -9.182 0.912 1.397 0.963 0.246 3.32 72.76 KMP

SF6 50.46 0.963 1.922 0.938 -7.880 0.994 1.363 0.979 0.253 4.80 65.74 HIGUCHI

SF7 47.74 0.929 1.949 0.969 -5.860 0.986 1.273 0.990 0.295 5.72 60.32 KMP

SF8 52.61 0.760 2.023 0.962 -4.618 0.891 1.220 0.933 0.334 6.06 56.23 FIRST

SF9 61.11 0.838 1.769 0.995 -11.33 0.944 1.473 0.986 0.218 3.53 70.79 FIRST

SF10 51.88 0.942 1.893 0.927 -8.693 0.992 1.380 0.984 0.246 3.88 69.56 HIGUCHI

SF11 62.12 0.886 1.777 0.986 -13.47 0.965 1.521 0.981 0.194 3.43 72.31 FIRST

SF12 76.06 0.694 1.407 0.917 -26.48 0.836 1.707 0.929 0.117 11.11 46.61 KMP



Table 8.18: Kinetic Data Derived from Various Kinetic Models for direct compressed Bilayer matrix tablets of Zolpidem Tartrate for

Biphasic Release

Formulation

Code


Best Fit

Model K0 R2 K0 R

2 KH R

2 KKP R

2 n

BF1 57.68 0.917 1.806 0.973 -11.58 0.985 1.463 0.993 0.214 6.34 58.18 KMP

BF2 54.82 0.904 1.775 0.988 -10.29 0.975 1.414 0.990 0.232 3.24 72.60 KMP

BF3 48.31 0.969 1.823 0.987 -8.291 0.994 1.358 0.971 0.244 8.58 55.17 HIGUCHI

BF4 59.43 0.920 1.726 0.995 -13.68 0.984 1.507 0.982 0.193 1.41 85.98 FIRST

BF5 44.18 0.936 1.831 0.992 -6.271 0.993 1.254 0.997 0.291 12.01 48.42 KMP

BF6 51.08 0.974 1.817 0.977 -9.577 0.989 1.412 0.955 0.224 6.20 60.62 HIGUCHI

BF7 62.60 0.909 1.862 0.914 -14.67 0.979 1.534 0.993 0.188 3.46 70.46 KMP

BF8 70.28 0.704 1.641 0.991 -14.84 0.846 1.580 0.924 0.178 9.08 50.77 FIRST

BF9 51.76 0.960 1.827 0.973 -9.497 0.995 1.400 0.983 0.233 5.11 65.12 HIGUCHI

BF10 62.53 0.879 1.758 0.988 -13.86 0.967 1.522 0.993 0.194 3.51 72.11 KMP

BF11 75.71 0.934 1.634 0.832 -33.87 0.990 1.736 0.983 0.103 10.26 46.72 HIGUCHI

BF12 79.45 0.839 1.441 0.996 -37.64 0.946 1.764 0.995 0.095 12.92 42.81 FIRST

BF13 83.84 0.934 1.384 0.946 -57.64 0.944 1.841 0.883 0.061 15.04 38.57 HIGUCHI

BF14 54.49 0.926 1.770 0.993 -10.73 0.990 1.425 0.997 0.225 3.44 73.95 KMP

BF15 61.62 0.967 1.725 0.972 -16.76 0.996 1.565 0.966 0.166 2.99 72.42 HIGUCHI



Table 8.19: Kinetic Data Derived from Various Kinetic Models for Compression Coated matrix tablets of Zolpidem Tartrate for

Biphasic Release

Formulation

Code


Best Fit

Model K0 R2 K1 R

2 KH R

2 KKP R

2 n

CCF1 73.28 0.816 1.755 0.967 -21.67 0.913 1.672 0.940 0.136 10.56 48.46 FIRST

CCF2 52.73 0.980 1.968 0.812 -10.06 0.997 1.427 0.971 0.222 4.58 67.12 HIGUCHI

CCF3 45.18 0.78 1.809 0.982 -8.316 0.997 1.329 0.978 0.245 13.70 45.64 HIGUCHI

CCF4 56.20 0.891 1.826 0.994 -9.673 0.971 1.421 0.985 0.235 1.69 85.07 FIRST

CCF5 44.08 0.933 1.802 0.996 -6.979 0.989 1.269 0.987 0.274 14.21 45.42 FIRST

CCF6 49.36 0.948 1.845 0.973 -8.038 0.994 1.344 0.990 0.257 6.41 60.07 HIGUCHI

CCF7 55.01 0.954 1.795 0.953 -11.53 0.995 1.452 0.987 0.212 3.31 73.29 HIGUCHI

CCF8 65.55 0.742 1.712 0.994 -11.76 0.880 1.506 0.957 0.209 6.68 56.73 FIRST

CCF9 55.70 0.934 1.812 0.971 -10.87 0.989 1.444 0.987 0.222 1.77 84.74 HIGUCHI

CCF10 47.21 0.962 1.862 0.983 -7.054 0.991 1.323 0.972 0.263 7.88 55.72 HIGUCHI

CCF11 56.60 0.893 1.777 0.977 -10.90 0.958 1.442 0.964 0.221 3.26 72.59 FIRST

CCF12 59.08 0.719 1.689 0.939 -7.544 0.861 1.374 0.933 0.364 5.59 60.78 FIRST

CCF13 79.46 0.667 1.417 0.934 -25.07 0.815 1.725 0.923 0.117 14.31 41.63 FIRST

CCF14 76.76 0.733 1.530 0.994 -24.66 0.876 1.698 0.961 0.127 12.29 44.75 FIRST

CCF15 63.63 0.932 1.649 0.982 -19.44 0.991 1.588 0.993 0.155 4.25 68.00 KMP



8.4.5 COMPARISON OF DISSOLUTION PROFILES

The similarity in the release profiles of marketed tablet as STILNOCT and all the

formulations was compared by making use of “Model Independent Approach”. A simple

model independent approach uses a difference factor f1 and similarity factor f2 to compare

dissolution profiles. Difference factors f1 and similarity factors f2 for all matrix

formulations of Zolpidem Tartrate prepared by wet granulation for monolithic matrix

tablets and direct compression for bilayer and compression coated matrix tablets with

different polymers were shown in Table 8.17 to 8.19.

8.4.5.1 SINGLE LAYER MONOLITHIC MATRIX TABLETS OF ZOLPIDEM

TARTRATE BY WET GRANULATION All formulations except SF3 and SF12 with 50 mg of HPMC K200M and 40 mg of Guar

gum of Single layer Monolithic matrix formulations showed (f2 ) value between 50 to 100

indicating similar release profiles of the formulations with marketed formulation. SF3 and

SF12 showed a similarity value below 50, indicating dissimilar release profiles. (Table

8.17) f2 value for the formulation SF5 with 30 mg of HPMC K200M was 72.76 and f1

value of 3.32 indicated more similarity of release profiles with marketed formulation and

was found to be optimised formulation for stability studies.

8.4.5.2 BILAYER MATRIX TABLETS OF ZOLPIDEM TARTRATE BY DIRECT

COMPRESSION

The drug release profile of formulations BF5 (20 mg of Carbopol 71G), BF11 (10 mg

Carbopol 971P), BF12 (20 mg Carbopol 971P) and BF13 (10 mg of Guar gum) produced

f2 value of 46.72, 42.81 and 38.57 indicating non similarity of release profiles.

Formulations BF3, BF8 indicated borderline similarity with f2 value of 55.17 and 50.77

respectively. All other formulations produced f2 value more than 50 indicating similarity

in release profiles with marketed formulation and were found to be more for formulation

BF4 as 85.98 with maximum similarity. Thus formulation BF4 with 10 mg of HPMC

K100M was optimized for stability studies.

8.4.5.3 COMPRESSION COATED MATRIX TABLETS OF ZOLPIDEM

TARTRATE BY DIRECT COMPRESSION

The formulations CCF1, CCF3, CCF5, CCF13 and CCF14 indicated non-similarity of

release profile of matrix tablets as per marketed formulation. All other formulations with



f2 value more than 50. Formulation CCF4 with 10 mg of HPMC K200M and f2 value of

85.07 was found to be optimized for stability studies.

8.4.6 STABILITY STUDIES:

Optimized formulations from in vitro drug release study, kinetics and similarity factor,

formulations SF5, BF4 and CCF4 with 30 mg for monolithic matrix tablets and 10 mg of

HPMC K200M for both Bilayer and Compression Coated tablets respectively were

subjected for stability studies. The results (Table 8.20) of drug content and dissolution

studies at 40°C / 75% RH, indicated no significant difference before and after stability

studies (p > 0.05).

Table 8.20: Drug Content after Stability studies

Formulation Code Time in days % Drug Content* % Drug release after 4 h*

SF5 0 99.27±0.03 92.42±0.48

30 98.68±0.68 92.03±0.75

60 98.33±0.32 91.74±1.11

90 98.18±1.31 91.17±1.29

BF4 0 102.39±0.44 93.49±3.94

30 101.93±0.76 93.05±0.24

60 101.59±0.25 92.85±1.56

90 100.17±1.13 92.86±1.42

CCF4 0 98.37±0.14 96.47±0.48

30 98.16±0.06 95.09±0.61

60 97.72±0.16 95.41±1.74

90 97.61±1.81 94.17±1.67


Chapter 8 Zolpidem Tartrate - Conclusion


8.5 CONCLUSION FOR ZOLPIDEM TARTRATE:

In the present study, we designed, prepared, and evaluated a biphasic release of drug from

suitable drug delivery system of Zolpidem Tartrate in the form of Single layer monolithic

matrix tablets, Bilayer tablets with IR layer compressed on CR layer and Compression

Coated matrix tablets with IR coat on the CR matrix core.

Proper combination of the immediate and controlled release phases for the

particular formulation method used would allow the optimization of the

immediate and controlled release dose fractions as a function of the drug

pharmacokinetics and metabolism.

Preliminary trials were taken for optimization of amount of superdisintegrant as

CCS for immediate layer in Single layer monolithic matrix tablets; for IR and CR

layers in Bilayer matrix tablets and Compression coated tablets.

To achieve biphasic release bilayer and compression coated matrix tablets

prepared by direct compression. Though direct compression method used, both the

systems are relatively complex with multiple manufacturing steps to combine

discrete immediate and controlled release components in the same dosage form.

Thus biphasic drug release of a commercial bilayer 12.5 mg Zolpidem tartrate

extended release tablet was mimicked by a simple monolithic matrix tablets that

incorporate a blend of immediate release granules based on HPMC K4M as a

binder, and controlled release granules based on different rate retarding polymers.

This simpler form of monolithic matrix tablets can be easily prepared using a

conventional tablet machine at high speed and could provide an alternative to the

commercially available bi-layered tablet.

Precompression parameters of powder and granules blend for IR and CR layers

and postcompression parameters of matrices shown acceptable results for all the

formulations.

Release profiles were governed by water uptake and tablet erosion in aqueous

media.

Matrices released the drug quickly by swelling of CCS in IR granules, layer or

outer compressible coat and the CR granules, layer or core (inner matrix tablet) of

rate retarding polymers provided a slow and controlled release of drug as per USP

requirements.

Chapter 8 Zolpidem Tartrate - Conclusion


The amount of CCS in IR layer of Single layer monolithic matrix tablets was less

as 20 mg in IR granules and was sufficient to give initial rapid release but in

bilayer and compression coated IR layer, CCS used was 40 mg.

Rate retarding polymer’s proportion required in single layer monolithic matrix

tablets was very high as 30 – 50 mg in CR granules; whereas only 10 – 20 mg of

polymer sufficient to control the drug’s biphasic release in bilayer and

compression coated matrices.

As compaction pressure required for formulation of bilayer and compression

coated matrices is more, CCS and lactose is required in CR layer to achieve

desired release profile which is not required in single layer monolithic matrices.

Optimally formulated matrices by all the three formulation methods with HPMC

K200M showed distinct biphasic release characteristics equivalent to

commercially available bilayered Stilnoct 12.5 mg tablet and give suitably desired

release profile as per USP criteria.

Formulation SF5 have similarity factor (f2=72.76), BF4 (f2=85.98) and CCF4

(f2=85.07) indicating good similarity in drug release pattern to that of marketed

product.

Short-term stability studies indicated no appreciable changes in the drug content

and in vitro drug release rates of formulation SF5, BF4 and CCF4.

Thus a rapid initial release of drug enables rapid initial absorption, rapid onset of

action and sleep induction. Due to controlled release properties of the formulation

the prolonged action and consequently sleep maintenance can be achieved.

Chapter 8 Zolpidem Tartrate - Bibliography


8.6 BIBLIOGRAPHY FOR ZOLPIDEM TARTRATE:

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Sublingual Zolpidem is more effective than oral Zolpidem in initiating early onset

of sleep in the post-nap model of transient insomnia: A polysomnographic study.

Sleep Medicine, 2009; 10: 616–20.

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systems, Marcel Dekker Inc., New York, 1978.

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Neuropsychiatric Disease and Treatment, 2007; 3: 5.

5. Basak S.C., Kumar K.S. and Ramalingam M., Design and release characteristics

of sustained release tablet containing metformin HCl, Brazilian J Pharm Sci,

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Acetaminophen Extended Release Tablet with Biphasic Release. At annual

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floating-bio adhesive tablets of Rosiglitazone Maleate. Asian Journal of

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Tablets of Salbutamol and Theophylline. Int. J. Pharm. Sci. and Nanotech. 2009;

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Chapter 8 Zolpidem Tartrate - Bibliography


13. Ishida M, Abe K, Hashizume M, Kawamura M. A novel approach to sustained

pseudoephedrine release: Differentially coated mini-tablets in HPMC capsules.

Int. J. Pharm. 2008; 359: 46–52.

14. Official monograph, Zolpidem tartrate, USP33, 28NF, Suppliment 2.

15. Abdul S, Poddar SS, A flexible technology for modified release of drugs: multi

layered tablets. J. Control. Rel. 2004; 97: 393–405.

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