Research Articles

2019  |  Vol: 5(1)  |  Issue: 1(January-February)  |  https://doi.org/10.31024/ajpp.2019.5.1.4
Formulation and evaluation of methylphenidate hydrochloride fast dissolving tablet by QbD approach

Shehla Khan*, Sadhana Shahi, Santosh Borde, Saliya Shaikh

Department of Pharmaceutics, Government College of Pharmacy, Aurangabad - 431005, Maharashtra, India

*Address for Corresponding Author

Shehla Khan

Department of Pharmaceutics,

Government College of Pharmacy, Aurangabad, (MH), India- 431005


Abstract

Objective: The aim of the proposed work was to apply quality by design (QbD) in the formulation and evaluation of methylphenidate HCl fast dissolving tablet using superdisintegrants for rapid dissolution of drug and absorption, which may produce rapid onset of action in the management of Attention deficit hyperactivity disorder (ADHD) with better patient compliance. Method: QbD assures pharmaceutical quality by understanding and controlling formulation and manufacturing variables ensuing as an advanced approach towards drug development. The study discusses elements of the QbD for development of methylphenidate HCl fast dissolving tablet via identifying quality target product profile, critical quality attributes, defining risk assessments, establishing design space, control strategy and product life cycle management &continuous improvement. FDT’s were prepared by direct compression method using Avicel PH 102 and Indion 234 as superdisintegrants to enhance its disintegration. A 32 full factorial design was applied to inspect the effect of  two independent variables i.e.,  concentration of Avicel PH 102 and concentration of Indion 234 on disintegration time (DT) and percentage drug release as dependent parameter. The compressed tablets were evaluated for hardness (kg/cm2), thickness (mm), friability (%), weight variation (mg), drug content (%), wetting time (s), disintegration time (s), and in-vitro drug release (%). Furthermore, analysis of variance (ANOVA), multiple regression analysis, 3D response graph and Overlay plot were successfully implemented to understand significant effects of both the variables on the selected responses. Result: All the FDT’s of all the formulation had drug content, weight variation, hardness and friability within USP limits. The optimized formulation showed percentage drug content of 98.88± 0.25%, wetting time of 23 ± 0.61 s, disintegration time of 14± 0.92 s and In-vitro drug release was found to be 98.14 ± 0.65 %. Conclusion: Thus, it can be conclude that formulation of Methylphenidate HCl FDT with increased dissolution rate and decreased disintegration time that dissolves rapidly in the mouth were prepared via implementation of QbD that could increase efficiencies and provide regulatory support.

Keywords: Methylphenidate HCl, quality by design (QbD), fast dissolving tablet (FDT), 32 factorial design, Attention deficit hyperactivity disorder (ADHD)


Introduction

The Center for Drug Evaluation and Research (CDER), US FDA defined Fast Dissolving Tablets (FDT) as “A solid dosage form containing medicinal substances or active ingredient which disintegrates rapidly, usually within a matter of seconds, when placed on the tongue.” Fast dissolving tablet has achieved better patient compliance over other conventional dosage forms especially for geriatric, pediatric, bedridden patients, patients who have swallowing difficulties (dysphagia) and for patients who are busy, travelling or have no access to water. Furthermore FDT may increase the bioavailability of some drugs due to absorption of drug in oral cavity and also due to pregastric absorption of saliva containing dispersed drugs that pass down into the stomach. As well as, the amount of drug that is subjected to first pass metabolism is reduced as compared to standard tablet (Khanna et al., 2016; Siddiqui et al., 2010; Kumar  et al., 2014; Jain and Naruka, 2009).

Quality by design (QbD) was first outlined by well-known quality expert M. Juran. The elements of QbD are depicted in figure 1. The QbD is a systemic approach to pharmaceutical development. It means designing and developing formulations and manufacturing processes to ensure pre-defined product quality. The information and knowledge gained from pharmaceutical development studies and manufacturing experience provides scientific understanding to support the establishment of the design space, product and process specifications, and manufacturing controls along with quality risk management. This ultimately leads to understand the impact of raw materials i.e. Critical Material Attributes (CMA), Critical Process Parameters (CPP) on the Critical Quality Attributes (CQA’s) (Chowdary et al., 2014; Wagh, 2015; Adepu and Bhogale, 2016).   

Figure 1.Elements of QbD  

The drug selected for preparation of FDT is Methylphenidate HCl which is a CNS stimulant used to treat medical conditions such as Attention Deficit Hyperactivity Disorder (ADHD) and narcolepsy. It inhibits the reuptake of dopamine and norepinephrine and therefore increased dopaminergic and noradrenergic activity in the prefrontal cortex which explain its efficacy in ADHD. Methylphenidate HCl is having oral bioavailability of 11-52% with half life of 4hours and possess first pass metabolism. Fast dissolving tablet of drugs avoids first pass metabolism which may improve the bioavailability as compared to conventional oral dosage forms along with quick onset of action (Tripathi, 2001).

Hence, the rationale was to formulate and evaluate fast dissolving tablets of Methylphenidate HCl by QbD approach using superdisintegrants for rapid dissolution of drug and absorption, in the treatment of ADHD with better patient compliance.

Material and methods

Methylphenidate HCl was received as gift samples from Ipca laboratories limited, Sejavta, M.P India. All the other excipients for FDT preparation were of analytical grade.

Identifying a Quality Target Product Profile (QTPP)

The quality target product profile (QTPP) as defined in ICH Q8 (R1) is “a summary of the quality characteristics or attributes of a drug product that ideally will be achieved and thereby ensure the safety and efficacy of a drug product.”

Critical Quality Attributes (CQA’s)

CQA’s as defined by ICH Q8 (R2) is a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality. CQA’s are generally associated with raw materials & process parameter. This parameter directly affects the quality of final product.

Quality risk assessment

It is one of the tools that help in identifying, scientifically evaluating, and controlling potential risks to quality. It also helps in continual improvement in the product and process performance throughout the product life cycle.

The main objective of risk assessment in pharmaceutical development is to identify which material attributes and process parameters affect the drug product CQA’s, that is, to understand and predict sources of variability in the manufacturing process so that an appropriate control strategy can be implemented to ensure that the CQA’s are within the desired requirements.

Formulation of Methylphenid​ate HCl FDT using 32 full factorial design

A 32 full factorial design was constructed where avicel PH 102 and indion 234 concentrations were selected as the independent variables. All formulation batches and a 32 full factorial experimental design summary are given in Table 1 and 2 respectively. The tablets were prepared by direct compression technique. The ingredients were weighed accurately as per the formula given in the table 1. The ingredients methylphenidate HCl, pearlitol SD 200, avicel PH 102 and indion 234 were passed through sieve # 40. All the above ingredients were mixed properly in polybag for 30 minutes. Aerosil and magnesium stearate were passed through sieve # 80, mixed properly and blended with initial mixture for 15 minutes. The powder blend was compressed into a tablet at an average weight of 100 mg using 6 mm concave punches in 12 station Karnavati rotary tablet machine (Borde et al., 2016; Bhusnure et al., 2015; Kshirsagar, 2014).    

Table 1. Formulation of factorial batches

Sr. No.

Ingredients

Factorial batches

F1

F2

F3

F4

F5

F6

F7

F8

F9

1

Methylphenidate  HCl

5

5

5

5

5

5

5

5

5

2

Avicel PH 102

2

7

2

5

7

5

2

5

7

3

Indion 234

2.5

4.5

4.5

3

3

2.5

3

4.5

2.5

4

Aerosil

2

2

2

2

2

2

2

2

2

5

Aspartame

3

3

3

3

3

3

3

3

3

6

SLS

3

3

3

3

3

3

3

3

3

7

Magnesium stearate

2

2

2

2

2

2

2

2

2

8

Pearlitol SD 200

80.5

73.5

78.5

77

75

77.5

80

75.5

75.5

Total weight

100

100

100

100

100

100

100

100

100

Evaluation of F​DT

The prepared tablets were evaluated for various parameters as follows:

Appear​ance and shape

The general appearance of the tablet includes the morphological characteristics like size, shape, color etc. Also tablets may have lines, break-marks and may bear a symbol or other markings.

Uniformity of thickness and diameter

The uniformity of the diameter and thickness was measured using vernier caliper. The average diameter and thickness of the tablets were calculated.

Hardness

Monsanto hardness tester was used to check the hardness of the tablet. The FDT was placed vertically between the jaws of the tester. The two jaws placed under tension by spring and screw gauge. By turning the screw, the load was increased and collapsed; the applied pressure from the spring was measured in kg/cm2.

Weight varia​tion

In weight variation test, 20 tablets from each batch formulation were weighed individually using an electronic balance, average weight was calculated and individual tablet weight was then compared with average value to find deviation in weight.

Friabil​ity

Friability was determined using Roche friabilator. A sample of pre-weighed 20 tablets was placed in Roche Friabilator, rotated at 25 rpm which was then operated for 100 revolutions. The tablets were then reweighed. A loss of less than 1 % in weight is generally considered acceptable.

Drug content

Twenty tablets were weighed and crushed to a fine powder. An accurately weighed sample equivalent to 5mg of methylphenidate HCl was taken in a volumetric flask. The content was dissolved in 100 ml pH 6.8 phosphate buffer. This solution was filtered through Whattman filter paper and respective dilution was done. The drug content was calculated by measuring the absorbance of the solution at 207.8 nm.

Wetting tim​e

Wetting time of dosage form is related with the contact angle. Wetting time of the fast dissolving tablet is another important parameter, which needs to be assessed to give an insight into capillarity and subsequently the disintegration properties of the tablets; a lower wetting time implies a quicker disintegration of the tablet.

A piece of tissue paper folded double was placed in a petri plate (internal diameter is 10 cm) containing 10 ml of 6.8 pH phosphate buffer. The tablet was placed on the tissue paper and allowed to wet completely. The time required for complete wetting of the tablet was then recorded in seconds.

Disi​ntegration time

The disintegration time for fast disintegrating tablet was determined in USP conventional disintegration test apparatus. The apparatus consist of 6 glass tubes that are 3 inches long, open at one end and held against 10 mesh screen at the bottom end of basket rack assembly. To test for disintegration time, one tablet were placed in each disintegration tubes and the basket arch is positioned in one liter beaker of water at 37 ± 2oC.

In-vitro dissolution study

The release rate of methylphenidate HCl from FDT (n=3) was determined using USP Apparatus 2 (Paddle). The dissolution test was performed using 900 ml of pH 6.8 phosphate buffer for 15 minutes at 50 rpm. The temperature of the medium was maintained at 37 ± 0.5ºC. Aliquot of 5 ml were withdrawn at an interval of 3, 6, 9, 12 and 15 minutes. The withdrawn samples were replaced with fresh dissolution medium. The samples were filtered through Whattman filter paper and analyzed spectrophotometrically at 207.8 nm (Bala, 2012; Lachman et al., 1991; Martin and Chun, 1994; Kumar et al., 2014; Patel et al., 2016).

Results and discussion

Identifying a Quality Target Product Profile (QTPP)

The target product profile describes the use, safety and efficacy of the product that initiates the development strategy.

The QTPP for Methylphenidate fast dissolving tablet is as given in Table 3.   

Table 2. Design summary

Factor

Independent variable

Units

Actual values

Coded values

Low

High

Low

High

X1

Avicel PH 102

mg

2

7

-1

+1

X2

Indion 234

mg

2.5

4.5

-1

+1

Table 3. QTPP for fast dissolving tablet formulation development

Profile component

QTPP target

Justification/ Remark/Rationale

In house Performed

Physical Attributes

Active ingredient

Same

Pharmaceutical equivalence requirement

No

Dosage form

Tablet

Pharmaceutical equivalence requirement: same dosage form

Yes

Route of administration

Oral

Pharmaceutical equivalence requirement: Same route of administration

Yes

Dosage design

Fast dissolving tablet which releases drug substance by disintegration

Fast dissolving tablet formulated for immediate drug release, to avoid gastric instability & first pass metabolism

Yes

Dosage strength

5 mg

Pharmaceutical equivalence requirement: Same strength

Yes

Tablet weight

100 mg

Manufacturability and patient acceptability

Yes

Stability

At least 24-month shelf-life at room temperature

For global regulatory filing and determining shelf life.

Yes

Appearance

Tablet confirming to description shape and size

Needed for patient acceptability

Yes

Drug product quality attributes

Physical attributes

Pharmaceutical equivalence requirement

Yes

 

Colour

Patient compliance

Yes

 

Odour

No unpleasant odour

Yes

 

Drug content

98-102%

Yes

 

Content uniformity

Within ± 15% and NMT ± 25%

Yes

 

Friability

NMT 1.0%

Yes

 

Disintegration

Within 30 seconds

Yes

 

Dissolution

Drug release NLT 90 % at 15 minutes in phosphate buffer pH 6.8.

Yes

Container closure system

Container closure system qualified as suitable for this drug product

Needed to achieve the target shelf-life & to ensure tablet integrity during shipping

No

Administration

The tablet can be taken without regard to food.

Food has no effect on absorption

No

Storage condition

Preserve in tight containers and store at room temperature.

Needed for stability

Yes

Chemical attributes

Identification

FTIR analysis

Needed for clinical effectiveness and safety

Yes

UV analysis

Needed for clinical effectiveness and safety

Yes

Assay for API

Not less than 98.0% & NMT 102.0%

Needed for clinical effectiveness

Yes

Biological attributes

Intended use

In treatment of Attention deficit hyperactivity disorder (ADHD) and narcolepsy.

It is a dopamine reuptake inhibitor in the CNS.

No

Critical quality attributes (CQA)

The initial CQA’s were defined from QTPP to identify satisfactory quality of the product. CQA is a physical, chemical, biological or microbiological property. Table 4, summarizes the CQA’s for methylphenidate HCl fast dissolving tablet formulation development. The assay, content uniformity, disintegration, dissolution and stability are identified as potential CQAs for formulation development that have an impact on formulation or process variables hence related to safety and efficacy. Therefore, these CQA’s were investigated and discussed in subsequent formulation development studies.

Table 4. Critical Quality Attributes (CQA’s) for fast dissolving tablet formulation development

Drug product

Target

CQA’s

Justification

In house performed

Physical attributes

Dosage form

Fast dissolving tablet

No

Not linked to safety and efficacy

Yes

Route of administration

Oral

No

Only related to patient compliance and acceptability

Yes

Strength

5 mg

No

Related to pharmaceutical equivalence requirement

Yes

Dosing frequency

Thrice a day

No

Only related to patient compliance and acceptability

Yes

Stability

Comply with ICH Q2R1

Yes

Related to efficacy of the product as shelf life hamper the product quality

Yes

Drug product quality attribute

Appearance

Color and shape acceptable to the patient. No visual tablet defects observed

No

Color, shape and appearance are not directly linked to safety and efficacy. Therefore, they are not critical

Yes

Odor

No unpleasant odor

No

In general, a noticeable odor is not directly linked to safety and efficacy

Yes

Weight variation

NMT 2 tablets should out of the range of ± 7.5% of 100 mg

Yes

It is carried out when the tablet has 90-95% of active ingredient

Yes

Friability

NMT 1.0% w/w

No

This target friability will not impact patient safety or efficacy

Yes

Identification

Positive for methylphenidate HCl

Yes

Identification is critical for safety and efficacy

Yes

Assay

98-102% w/w

Yes

Assay variability results in dose fluctuation and hampers safety and efficacy

Yes

Content uniformity

Within ± 15% and NMT ± 25%

Yes

Ensure consistency of dose deliver to the patient, hence impact on safety and efficacy

Yes

Hardness

Low

No

Critical for dissolution profile

Yes

Disintegration

Within 30 seconds

Yes

Failure to meet the disintegration time can impact on efficacy

Yes

Dissolution

Immediate but complete drug release phosphate buffer (pH 6.8)

Yes

Dissolution can impact on bioavailability and ultimately efficacy

Yes

Quality Risk assessment

To estimate the impact of CQA in product development a risk assessment of the drug substance was carried out. Initial risk assessment for formulation component & Operation variables was determined in table 5. Justification for assigned risk was summarized in table 6.

Table 5. Initial risk assessment for formulation component & operation variables

Drug Product CQAs

Formulation Variables

Operation  Variables

API Particle size

MCC particle size

Blending & lubrication

Compression

Press speed

Assay

Medium

Low

Medium

High

Low

Content uniformity

High

Medium

High

High

High

Disintegration Time

High

High

Medium

High

High

Drug release

High

High

Medium

High

High

Table 6. Justification for risk assessment of CQA for FDT development

Process steps

Drug product CQAs

Assigned Risk

Justification

Blending and lubrication

Assay

Medium

Blending and lubrication may cause variable flowability of the blend affecting assay.

Content uniformity

High

The PSD and cohesiveness of the drug substance adversely impact its flowability. If not blended properly with excipients, it may affect CU.

Disintegration time

Medium

Blending process variables may impact the distribution of CCS in the blend which could impact disintegration of the granules.

Drug release

Medium

Blending process variables may impact the distribution of CCS in the blend which could impact disintegration of the granules and ultimately, dissolution of the tablets.

Compression force

Assay

High

Assay is dominated by BU and flowability.

Content uniformity

High

CU is dominated by BU and flowability and is unrelated to main compression force

Disintegration time

High

Suboptimal compression force may affect tablet hardness and friability and, ultimately, disintegration.

Drug release

High

Suboptimal compression force may affect tablet hardness and friability, disintegration and, ultimately, dissolution

Press speed

Assay

Low

A faster than optimal press speed may cause inconsistent die filling and weight variability which may then impact CU, disintegration and dissolution. For efficiency, the press speed will be set as fast as practically possible without adversely impacting tablet quality.

Content uniformity

High

Disintegration Time

High

Drug release

High

Degradation Products

Medium

Design of experiment for formulation of methylphenidate HCl FDT using 32 full factorial design

A 32 full factorial design was used to optimize fast dissolving tablets of methylphenidate HCl using an experimental design program Design Expert 7 via direct compression method. Avicel PH 102 concentration (X1) and indion 234 concentration (X2) were selected as the independent factors and disintegration time (DT) and % drug release as a response i.e., dependent variable and experimental trials were performed for all nine possible combinations.. The levels of the two factors were selected on the basis of the preliminary studies carried out before implementing the experimental design.

Evaluation of FDT for methylphenidate HCl

The prepared fast dissolving tablets were evaluated for various parameters like weight variation, hardness, friability, thickness, wetting time, disintegration time (DT), assay and readings were recorded. All the formulation batches showed the results in the desired range as given in table 7.

Table 7. Evaluation of FDT for methylphenidate HCl

Batches

Weight variation (mg± SD)*

Hardness (Kg / cm2) ± SD*

Friability (%)*

Thickness (mm ± SD)*

Wetting time (s)*

DT (s)*

Assay (% )*

F1

99.89±0.47

3.5 ± 0.17

0.34±0.08

2.47 ± 0.06

30 ± 0.21

26 ± 0.71

98.87± 0.21

F2

98.11±0.53

3.7 ± 0.21

0.44±0.02

2.50 ± 0.05

51 ±0.10

47 ± 0.52

98.60± 0.09

F3

101 ± 1.06

3.4 ± 0.80

0.36±0.05

2.54 ± 0.05

27 ± 0.31

23 ± 0.67

101.1± 0.40

F4

98.18±0.85

3.4 ± 0.49

0.29±0.08

2.44 ± 0.08

25 ± 0.72

21 ± 0.78

98.67± 0.31

F5

100 ± 0.78

3.5 ± 0.52

0.41±0.05

2.45 ± 0.09

35 ± 1.04

31 ± 0.57

98.54± 1.01

F6

100 ± 0.55

3.6 ± 0.23

0.35±0.90

2.58 ± 0.02

40 ± 0.22

36 ± 0.82

100± 0.07

F7

99.93±0.83

3.4 ± 0.61

0.37±0.07

2.50 ± 0.09

23 ± 0.61

14 ± 0.92

98.40± 0.19

F8

101 ± 0.77

3.7 ± 0.84

0.42±0.01

2.43 ± 0.05

31 ± 0.81

24 ± 0.89

98.43± 0.11

F9

98.07±1.33

3.8 ± 0.49

0.38±0.07

2.55 ± 0.10

61 ±0.43

57 ± 0.49

98.37± 0.38

*mean ±standard deviation (SD), n=3

In- vitro dissolution study

FDT showing lower disintegration time will be evidence for high drug release. Drug release of formulation F1-F9 was depicted in table 8. For factorial batches F1 to F9 the drug release was in the range of 80.12 to 98.14%.  

Table 8. In-vitro dissolution drug release of formulation F1-F9*

Time (min)/ Batches

F1

F2

F3

F4

F5

F6

F7

F8

F9

0

0.00

0.00

0.00

0.00

0.00

0.00

0.00

0.00

0.00

3

25.67±0.35

24.8±1.22

27.97±0.67

26.78±0.33

24.4±1.86

25.19±0.44

27.57±1.98

28.76±0.35

24±2.45

6

49.69±1.22

39.73±1.77

46.9±0.56

46.89±1.03

43.69±1.45

40.52±0.87

48.13±1.35

47.7±0.76

38.93±0.65

9

58.84±1.44

56±1.02

59.67±1.45

60.05±0.87

59.21±0.46

57.59±0.17

61.42±1.87

60.08±0.98

52.01±0.44

12

73.31±0.89

72.46±1.65

76.53±1.32

78.5±0.56

72.49±0.98

69.27±1.64

76.55±0.76

76.55±0.99

64.43±1.54

15

91.1±0.99

83.89±1.44

94.11±1.22

96.11±1.45

89.11±1.65

86.26±1.22

98.14±0.65

93.09±0.89

80.12±1.22

*mean ±standard deviation (SD), n=3          

In-vitro dissolution profile (Figure 2) revealed, F7 batch containing 3% indion 234 and 2% avicel PH102 gave maximum drug release i.e., 98.14% amongst factorial batches. Hence it was evident that increase in concentration of avicel PH 102 the drug release from tablet was found to be decreased but in case of indion 234 at middle concentration gave highest drug release. 

Figure 2. Percentage Cumulative drug release of all formulation batches (F1-F9)

 

Analysis of data by design expert software

ANOVA study

The analysis of variance (ANOVA) and multiple regression analysis were done using Stat-Ease Design Expert 7.1.4 software. The statistical treatment and interpretation of data were essential steps where the p-value indicated main effects on optimization of formulation. P values of co-efficient of X1 and X2 indicated the model significant, since the p value was found to be less than 0.05 i.e., (*p<0.05). Therefore, established the significant effect of both the variables on the selected responses considering both the variables caused significant change in the responses.  

Validation of the experimental design

A statistical model incorporating interactive and polynomial terms was utilized to evaluate the responses.

                            Y=b0+b1 X1+b2 X2+b12 X1X2+b11X12+b22X22

Where, Y is the dependent variable, b0 is the arithmetic mean response of the nine runs and bi(b1,b2,,b12,b11 and b22) is the estimated coefficient for the corresponding factor Xi (X1,X2,X12,X11, and X22), which represents the average results of changing one factor at a time from its low to high value. The interaction term (X1X2) depicts the changes in the response when two factors are simultaneously changed. The polynomial terms (X12 and X22) are included to investigate nonlinearity.

The fitted regression equations relating the responses DT and Drug release are shown in the following equations, respectively.

DT = + 277.40958 – 6.42348* Avicel PH 102 – 147.6839 * Indion 234 - 0.41296 * Avicel PH 102 * Indion 234 + 1.40000 * Avicel PH 1022 + 20.77778 * Indion 2342                                   

                                                    (R2 = 0.9497)

The first variable X1 (Avicel PH 102 concentration) and the second variable X2 (Indion 234 concentration) showed negative sign indicating negative effect on DT. R2 value 0.9497 for disintegration time indicated the adequate fitting of the quadratic model.

% Drug release = -31.13662 + 2.91419 * Avicel PH 102 + 71.9959 * Indion 234 +0.0627 * Avicel PH 102 * Indion 234 - 0.57100* Avicel PH 1022 – 10.00333 * Indion 2342                                           

                                                      (R2 = 0.9829)

The first variable X1 (Avicel PH 102 concentration) and the second variable X2 (Indion 234 concentration) both showed positive sign indicating positive effect on drug release. R2 value 0.9829 for drug release indicated the adequate fitting of the quadratic model.

Response sur​face plot

The relationship between the response and independent variables can be directly visualized from the response surface plots. A 3D response surface plot was generated in which the responses were represented by curvature surface as a function of independent variables to study the effects of independent variables on response DT and drug release. The 3D response surface plot of factorial variable on disintegration time and Drug release are as shown in figure 3(A) and 3(B) respectively.  

Figure 3. 3D Response surface plot of factorial variable on disintegration time (A), Drug release (B)  

Validation of optimized formulation

To validate the model, a formulation from design space with 2.2 mg Avicel PH 102 and 3 mg Indion 234 were selected. The optimized formulation selected was prepared to obtain the predicted and experimental values of all the response variables i.e., disintegration time and percentage drug release. The tablet properties were evaluated and found within limits (Table 9). The predicted and observed experimental values of responses were obtained which showed close resemblance depicting the validity of the chosen formulation and attaining desired QTPP for fast dissolving tablet of methylphenidate HCl (Table 10).

Table 9. Evaluation of optimized batch

Batch

Weight variation (mg ± SD)*

Hardness (Kg / cm2) ± SD*

Friability (%)*

Thickness (mm ± SD)*

Wetting time (s)*

Assay (% )*

Optimized batch

100 ± 0.53

3.4 ± 0.75

0.33±0.09

2.49 ± 0.07

23 ± 0.61

98.88± 0.25

*mean ±standard deviation (SD), n=3

Table 10. Comparison of predicted and obtained values of optimized formulation

Responses

Optimized formulation

Predicted

Experimental (Optimized)*

DT (s)

12

14 ± 0.92

Drug release (%)

98.14

98.14 ± 0.65

*mean ±standard deviation (SD), n=3

Design space

ICH Q8 (R2) defines design space as the multidimensional combination and interaction of input variables and process parameters that have been demonstrated to provide assurance of quality. Concentration of avicel PH 102 and indion 234 was found to be critical on responses DT and % cumulative drug release. Based on the requirement of product quality the criteria considered for responses was DT not more than 30 seconds and drug release not less than 90% at 15 minutes. This study leads to the design space from multidimensional combination of Avicel PH 102 and Indion 234 to the acceptable operating ranges for formulating fast dissolving tablet with respect to target product profile. When critical variables operated within the established design space compliance to CQAs would be assured. Design space (Overlay plot) shown in Figure 4 had shaded region with yellow color indicates that region of successful operating ranges.   

Figure 4. Overlay plot

 

Control strategy

Control strategy is defined as “a planned set of controls, derived from current product and process understanding that assures process performance and product quality”. It helps in avoiding defect & maintaining desired quality. These studies investigated the material attributes and process parameters that were deemed high risk to the CQAs of the drug product during the initial risk assessment. The control strategy of methylphenidate HCl FDT for process parameters included assay, concentration of Avicel PH 102 and Indion 234, weight variation, hardness and thickness for which the acceptable operating ranges were established.

Product life cycle management &continuous improvement

Continuous improvement is a vital element in a modern quality system that aims at increase efficiency by optimizing a process and eliminating wasted efforts in production. Upon approval, the manufacturing process for methylphenidate HCl fast dissolving tablets will be validated using the lifecycle approach that employs risk-based decision making throughout the drug product lifecycle as defined in the FDA process validation guidance. Throughout the product lifecycle, the manufacturing process performance will be monitored to ensure desired quality attributes are achieved. If any unexpected process variability is detected, appropriate actions will be taken to correct, anticipate, and prevent future problems so that the process remains in control.

Conclusion

From the findings, it may be concluded that, fast dissolving tablet of methylphenidate HCl by QbD approach can be successfully prepared by direct compression techniques using selected superdisintegrants for the better patient compliance and effective therapy. Implementing QbD concept provided a systematic approach in FDT development emphasizing on product and process understanding and process control to ensure predefined product quality objectives. In the present study initial risk assessment was done and QTTP, CQA for fast dissolving tablet was identified. Concentration of Avicel PH 102 and Indion 234 was identified as critical parameters to achieve desired QTPP. Also disintegration time and in vitro dissolution was found to be a CQA for the development of FDT.

And thus, this CQA was optimized using 32 full factorial design. The selected independent variable exhibits significant effect on dependent variables like drug release and DT. Polynomial equations, ANOVA, different statistical values were utilized to interpret significance of formulation parameters on responses and design space was proposed with desired QTPP. The validation of optimized formulation showed close resemblance depicting the validity of the chosen formulation and attaining desired QTPP for fast dissolving tablet of methylphenidate HCl Graphical presentation of the data using response surface plot helps to show the relationship between the response and the independent variables. The information given by graph was similar to that of mathematical equations obtained from statistical analysis.

From the experiments, it can be concluded that if formulation parameters were operated within the proposed design space, high risk can be converted to low level of risk. The formulation prepared within design space resulted in formulation with acceptable disintegration time and percentage drug release. Hence, finally it can be concluded that formulation of fast dissolving tablets of methylphenidate HCl which disintegrates and disperses in saliva within 30 seconds and showed more than 90 % cumulative drug release  is a promising approach for the treatment of Attention deficit hyperactivity disorder (ADHD).

Acknowledgements

The authors are thankful to the principal and Dr. S. R Shahi, Government College of Pharmacy, Aurangabad for making the facilities available to us.

Conflict of interests

Declared none

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