QbD-enabled systematic development of gastroretentive multiple-unit microballoons of itopride hydrochloride

Figures & data

Table 1. Quality target product profile (QTPP) for GR hollow microballoons of ITH.

QTPP elements	Target	Justification
Dosage form type	Gastroretentive system	Helps in maintaining the therapeutic effect of drug for prolonged periods of time by retaining the formulation in GIT for extended time periods
Drug delivery type	Microballoons	Selection of GR floating microballoons help in enhancing the residence time of drug formulation in stomach and upper GIT leading to complete absorption of drug within its absorption window
Route of administration	Oral	Recommended route for delivery of ITH is oral and the available marketed formulations (i.e. tablets) are also meant for oral intake only
Dosage strength	150 mg	It is the unit dose of ITH which needs to be incorporated for once-a-daily administration
Packaging	Hard gelatine capsules	The microballoons can easily be delivered by filling in hard gelatin capsules with improved patient compliance, portability and manufacturing ease
Stability	At least 24 months at room temperature	To maintain therapeutic potential of the drug during storage period

GI, gastrointestinal; GR, gastroretentive; ITH, itopride hydrochloride.

Table 2. Critical quality attributes (CQAs) for GR hollow microballoons of ITH and their justifications.

Quality attributes of the drug product	Target	Is this a CQA?	Justification
Physical attributes
Color	Acceptable to patients	No	Color, odor and appearance were not considered as critical, as these are not directly linked to patient efficacy and safety.
Odor	No unpleasant order
Appearance	Acceptable to patients
Drug content	100%			No	Drug content is a vital parameter for any pharmaceutical dosage form for attaining maximal plasma concentration of the drug. Unlike tablets, microballoons are not the unit dose formulations, thus it was regarded as moderately critical.
Percent buoyancy	100%	No	Higher value of percent buoyancy is required for longer residence time of the drug formulation in the gastric region. As the developed GR microballoons were hollow in nature having inherent ability to completely float upto 24 h, hence it was taken up as less critical.
Particle size	Low	Yes	As the microballoons are administered through oral route, the particle size was thought to exert significant influence in attaining prolonged gastric retention of the drug formulation, and thus its therapeutic performance. Hence, it was considered as critical.
Entrapment efficiency	100%	Yes	Higher values of entrapment efficiency is vital for accomplishing maximal drug release regulation from the dosage form and hence the therapeutic concentration of the drug. Thus, it was considered as critical.
Time required for 60% drug release (T60%)	∼8 h	Yes	This parameter is an indicator of sustained release profile of drug release from the prepared microballoon formulations, thus was taken up as highly critical.
Cumulative amount of drug release in 18 h (Q18h)	∼75.0%	Yes

Table 3. Formulation and process variables with their respective high and low levels investigated employing Taguchi design.

Runs	Drug: polymer ratio	Stirring temp.	Stirring speed	Vol of HLP	Vol of acetone	Vol of aq: MeOH	Stirrer type
1	+1	+1	−1	+1	−1	+1	+1
2	−1	+1	+1	−1	+1	+1	+1
3	−1	−1	−1	−1	−1	−1	+1
4	+1	−1	+1	−1	−1	+1	−1
5	+1	+1	−1	−1	+1	−1	−1
6	−1	+1	+1	+1	−1	−1	−1
7	+1	−1	+1	+1	+1	−1	+1
8	−1	−1	−1	+1	+1	+1	−1
				Levels
Levels of the factors studied				Low (−1)		High(+1)
Drug–polymer ratio (mg)				1:1		1:5
Stirring temperature (°C)				25		35
Stirring speed (rpm)				600		1000
Volume of HLP (mL)				40		60
Volume of acetone (mL)				06		12
Volume of aqueous-MeOH (mL)				0.2		0.6
Stirrer type				Mechanical stirrer		Magnetic stirrer

HLP, high-density liquid paraffin; MeOH, methanol; rpm, revolutions per minute.

Table 4. Formulation composition of GR hollow microballoons prepared as per BBD.

Code	Trial	Factor 1	Factor 2	Factor 3
TA	1	0.00	0.00	0.00
TB	2	0.00	1.00	1.00
TC	3	0.00	−1.00	1.00
TD	4	1.00	0.00	−1.00
TE	5	1.00	−1.00	0.00
TF	6	−1.00	−1.00	0.00
TG	7	1.00	0.00	1.00
TH	8	0.00	0.00	0.00
TI	9	−1.00	0.00	1.00
TJ	10	0.00	1.00	−1.00
TK	11	0.00	0.00	0.00
TL	12	0.00	0.00	0.00
TM	13	0.00	−1.00	−1.00
TN	14	−1.00	0.00	−1.00
TO	15	0.00	0.00	0.00
TP	16	−1.00	1.00	0.00
TQ	17	1.00	1.00	0.00
Translation of coded factors into physical units
		Coded levels
Factors		−1	0	1
Drug: Polymer ratio		1:3	1:3.5	1:4
Stirring temperature (°C)		25	30	35
Stirring speed (rpm)		600	800	1000

Figure 1. Ishikawa fish-bone diagram depicting the cause-and-effect relationship among the formulation and process variable for formulation of GR hollow microballoons of ITH.

Table 5. REM for initial risk assessment of GR hollow microballoons of ITH.

Table 6. Summary of FMEA analysis illustrating RPN scores for various formulation and process variables affecting the CQAs.

Sl. no.	Failure modes	Severity (S)	Occurrence (O)	Detection (D)	RPN (S O D)	Consequences on CQAs
1	Drug–polymer ratio	8	6	6	288	Yield, Size, EE, Q18, T60
2	Polymer type	5	4	2	40	Q18, T60
3	Vol. of acetone	6	6	5	180	Yield, Size, EE
4	Vol. of aq. phase	5	5	5	125	Yield, Size, EE
5	Vol. of MeOH	7	6	5	210	Yield, Size, EE
6	Volume of HLP	7	4	5	140	EE, Q18, T60
7	Stirrer type	6	5	5	150	Size, Q18, T60
8	Stirring speed	7	7	4	196	Yield, Size
9	Temperature	6	5	4	120	Size, EE
10	Stabilizer conc.	4	3	2	24	Yield, EE
11	pH	3	2	2	12	Yield, Size, EE

EE, entrapment efficiency; Q_18h, cumulative amount of drug release in 18 h; T_60%, time required for 60% drug release.

Figure 2. Pareto charts for screening of influential factors as per Taguchi design using chosen critical quality attributes (CQAs), (A) percent yield, (B) entrapment efficiency, (C) floating time.

Table 7. Coefficient of model terms and statistical parameters obtained for second order quadratic equations for the studied CQAs.

	Polynomial coefficients for CQAs
Coefficient code	Entrapmentefficiency	Particle size	Q18h	T60%
β0	+87.18	448.16	+69.4	+8.86
β1	−0.725	196.54	−16.7125	+5.16625
β2	+3.8	−2.03	−1.5875	+0.1525
β3	+3.6	−20.94	+1.625	−0.13875
β4	−0.15	−4.58	+0.175	−0.03
β5	+1.2	−11.95	−0.75	−0.0475
β6	+1.25	−11.58	+1.5	−0.375
β7	+4.685	−93.83	+10.0125	−3.25875
β8	−5.015	1.65	−0.2375	+0.04375
β9	−2.915	4.17	+0.8375	−0.02875
Model p value	p < 0.0001	p < 0.0001	p < 0.0001	p < 0.001
R^2	0.9831	0.9974	0.9805	0.9961
PRESS	53.41	96.47	28.19	64.03

PRESS, predicted error sum of squares.

Figure 3. Response surface plots showing the influence of CMAs and CPPs, i.e. amount of polymer, stirring temperature and stirring speed on CQAs, (A) EE, (B) particle size, (C) T_60% and (D) Q_18h of GR microballoons of ITH.

Figure 4. Linear correlation plots and residual plots between the observed and predicted values of various CQAs, (A–B) entrapment efficiency, (C–D) particle size, (E–F) T_60% and (G–H) Q_18h.

Figure 5. Dissolution profiles of optimized GR microballoon formulation of ITH and marketed tablet (Ganton). The inset depicts mean rate of drug release versus mid-point of time intervals from optimized microballoons vis-à-vis the marketed tablet.

Figure 6. Scanning electron microscopy images of the optimized GR hollow microspheres.

Figure 7. FTIR spectra of pure drug, Eudragit S-100, physical mixture of drug and polymer, and optimized microballoon formulation.

Figure 8. DSC thermograms of pure drug, Eudragit S-100, physical mixture of drug and polymer, and optimized GR microballoons.

Figure 9. PXRD patterns of pure drug, Eudragit S-100, physical mixture of drug and polymer, and optimized GR microballoons.

Figure 10. X-ray images of the rabbit stomach, (A) without microballoons, (B) with barium meal, (C) after 30 min administration of microballoons, (D) after 2 h administration of microballoons, (E) after at 3 h administration of microballoons, (F) after 4 h administration of microballoons, (G) after 6 h administration of microballoons, (H) after at 8 h administration of microballoons.