A Quality by Design Approach to Optimize Tablet Formulations containing PVP
VA64 Amorphous Dispersions: Formulation Variables
Pranjal Taskar, Heather Bouck, Brian Greco, Hong-Guann Lee, Kat Brookhart, Sanjay Konagurthu
pranjal.taskar@thermofisher.com | sanjay.konagurthu@thermofisher.com
Thermo Fisher Scientific

PURPOSE• Amorphous solid dispersions (ASDs) manufactured using techniques suchas hot-melt extrusion, co-precipitation and spray drying help enhance API
bioavailability• Polymers such as Polyvinyl pyrrolidone co-vinyl acetate 64 (PVP VA64)
and Polyvinylpyrrolidone (PVP K30) often lead in screening experiments
due to stability enhancement, solubilization and crystallization inhibition
capabilities• However, hydrophilic polymers as such have strong binding and gelation
properties, which frequently presents a disintegration/dissolution
performance challenge for dosage forms

NO

•

n
Kollidon K30 (Povidone)
Polyvinylpyrrolidone

Tablets demonstrate a viscous
layer on the outside withdefined boundaries (gel block)and a dry tablet core

Water penetration to the tablet
core blocked, hinderingformation of primary particles

LongDisintegrationTimes

OBJECTIVE(S)The goal of this work is to utilize a Quality by Design (QbD) approach to generate a design space for tablet
formulations of PVP VA64 ASDs
1. Evaluate different formulation variables to identify main effects and their impact on the tablet criticalquality attributes (CQA) (dependent variables/responses)
2. Evaluate tableting additives such as inorganic salts and dietary sugars and impact on tablet CQAMETHOD(S)••••Master formulae for all the 16 formulations are listed in Table 1.
The formulations were manufactured by a bench-scale dry granulation process as depicted in Fig 3

8-run screening design (Fig 1) was generated with a D-optimality criterion•
Different type of filler and disintegrant (Categorical variables, Fig 2)•
MCC: Filler ratio (% MCC, 33 – 67%) and Disintegrant (5-15%) loading (Continuous variables)•
MCC was utilized across all formulations as the ductile filler in a ratio with the brittle fillers as we tried
to optimize this ratio•% Intragranular addition was maintained around 90% (monitored, not included in the initial screen)
Design was augmented with 6 additional runs to study certain effects in further detail•
Limits on % Disintegrant were narrowed (8-10%)•
Limits on % MCC were expanded (20-80 %)•Limits on % Intragranular addition were expanded (60-90%)
This data was fit using Standard Least Squares.

Fig 4. Effects of different independent variables ontableting CQA based on the screening DOE

Fig 6. Hydrophilic matrix gelling phenomenon:
Impact of presence of inorganic salt in
disintegration on hydrophilic tablet matrices:Time series fluorescence images of hydrating
HPMC matrix with (left) 0.008% w/v Congo Redand (right) NaCl with 0.008% w/v Congo Red

Fig 3. Process train used for manufacture of tablets
Blend
Turbula Blender

Kollidon VA-64 (Copovidone)
vinylpyrrolidone-vinyl acetate
copolymer

Water-soluble polymers such as
HPMC, Soluplus andcopovidone reportedly depict
gelling phenomenon

Inorganic Salts- NaCl speeds disintegration time of tablets containing hydrophilic matrices

METHOD(S)

SlugSingle Station Press

De-Lump20 Mesh Sieve

Blend
Turbula Blender

MillVector TFC Lab-Micro MillCompression
Single Station Press

Table 1. Master Formulae for 14 formulations from the DOE and 2 additional runs with formulation
additivesPrototype Formulations
F1F2F3F4F5F6Component
40:60 Z160:PVP-VA64 ASD

35.00%

35.00%

35.00%

35.00%

35.00%

Microcrystalline Cellulose (Avicel PH-105)

14.14%

33.67%

11.00%

27.00%

Lactose Monohydrate (FloLac 90)
Emcompress (DCP)
Parteck M100 (Mannitol)
Kollidon CL-SF (Crospovidone)
Kollidon CL (Crospovidone)
Croscarmellose Sodium (Ac-Di-Sol)
Sodium Chloride (Powder Grade)
Sucrose (Di-Pac Tableting Sugar)
Colloidal Silicon Dioxide
PRUV SSF
Intragranular Total

38.86%
2.50%
1.00%
0.50%
92.00%

19.33%
2.50%
1.00%
0.50%
92.00%

5.00%

5.00%

Microcrystalline Cellulose (Avicel PH-200)
Parteck M200 (Mannitol)
Kollidon CL-SF (Crospovidone)
Kollidon CL (Crospovidone)
Croscarmellose Sodium (Ac-Di-Sol)
Sodium Chloride
SucrosePRUV SSF
Extragranular Total
Total

F7F11F12F13F14F15F16

35.00%

F8F9F10Unit Composition (by weight %)35.00%
35.00%
35.00%
35.00%

35.00%

35.00%

35.00%

35.00%

35.00%

35.00%

27.00%

33.67%

21.50%

11.00%

9.75%

18.50%

3.90%

15.60%

12.66%9.62%

9.62%

12.66%

32.00%
7.50%
1.00%
0.50%
87.00%

16.00%
7.50%
1.00%
0.50%
87.00%

16.00%
7.50%
1.00%
0.50%
87.00%

19.33%
2.50%
1.00%
0.50%
92.00%

26.50%
5.00%
1.00%
0.50%
89.50%

32.00%
7.50%
1.00%
0.50%
87.00%

9.75%
4.00%
1.00%
0.50%
60.00%

18.50%
4.00%
1.00%
0.50%
77.50%

15.60%
4.00%
1.00%
0.50%
60.00%

3.90%
4.00%
1.00%
0.50%
60.00%

35.34%
5.00%
1.00%
0.50%
89.50%

28.38%
5.00%
5.00%
1.00%
0.50%
84.50%

28.38%
5.00%
5.00%
1.00%
0.50%
84.50%

25.34%
5.00%
1.00%
0.50%
79.50%

5.00%

5.00%

5.00%

5.00%

5.00%

5.00%

17.75%
17.75%

9.00%
9.00%

7.10%
28.40%

28.40%
7.10%

5.00%

5.00%

5.00%

5.00%
10.00%

4.00%

4.00%

4.00%

4.00%
5.00%

5.00%
5.00%

5.00%

5.00%

5.00%
0.50%
15.50%
100.00%0.50%
20.50%
100.00%

2.50%
7.50%

7.50%

7.50%

0.50%
8.00%
100.00%

Response

7.50%

2.50%

0.50%
8.00%
100.00%

Table 2. Analysis of Variance results determining significanceof different effects for response variables

0.50%
13.00%
100.00%

5.00%
2.50%

0.50%
13.00%
100.00%0.50%
13.00%
100.00%

0.50%
8.00%
100.00%0.50%
10.50%
100.00%0.50%
13.00%
100.00%0.50%
40.00%
100.00%0.50%
22.50%
100.00%0.50%
40.00%
100.00%0.50%
40.00%
100.00%0.50%
10.50%
100.00%0.50%
15.50%
100.00%RESULTSDESIGN OF EXPERIMENTS• As depicted in Table 2., Disintegrant Type, % Disintegrant, and Filler Type had a statistically significant impact on the DT (min)whereas % MCC loading had a statistically significant impact on Tensile Strength (MPa)Disintegration
Time (min)Tensile Strength(MPa)

Effect Tests

P-value

Disintegrant Type0.0092% DisintegrantFiller Type0.00020.0027

MCC: Filler Ratio (%MCC)

0.0214

Ref: Microstructural imaging of early gel layer formation in
HPMC matrices, Journal of Pharmaceutical Sciences, Vol.
95, No. 10, October 2006

Fig 5. 40:60 Z-160:PVP-VA64 ASD Tablet Characterization: Non-sink dissolution performance for select formulations• Fig 4 depicts the effects of different responses:• Ac-Di-Sol demonstrated quickest DT with good tensile strength, making it most desirable• With the use of Kollidon CL-SF, we observe steady increase in DT• We observe speeding of DT with increase in % Disintegrant, however we see that this effect plateaus at ~9% from the Desirabilitygraph• Mannitol is the most desirable Filler; this can be attributed to quicker DT and comparable Tensile strength.

Mannitol

Independent Variables

Type of filler used
MCC: Filler ratio% MCC% Intragranular• % Intragranular does not impact DT, however a slight trend is observed with loss in tablet tensile strength as we add morematerial intragranularly• % MCC loading does not impact DT, however, a greater MCC: Filler ratio increases the tensile strength of the formulation

NON-SINK DISSOLUTION

Lactose• F4 & F5 demonstrated 1.2 times increase in AUC over the neat ASD (Fig 5) – high level of disintegrating agent (15%) regardlessof the disintegrating agent typeDCP• F14 demonstrates 1.4 times increase in AUC over the neat ASD - presence of NaCl speeds DT. The rationale behind this can beseen in Fig 6, wherein researchers demonstrate quicker penetration of water in hydrophilic matrices in the presence of NaCl
• F7, F13 and F15 have 10% disintegrant, slowing DT (>210 min) and in turn the drug released

Kollidon CL• Disintegrant type, MCC: Filler Ratio did not impact the slow release• Presence of dietary sugar additive, Sucrose, did not help this formulation

Disintegrant Type

Kollidon CL-SF

CONCLUSIONS% Disintegrant

Dependent Variables

Fig 1. 8-run Screening Designat different levels ofindependent variables

Fig 2. Independent and dependent
variables as a part of the screening
studyAc-Di-Sol

1.

Disintegration Time(DT)2.

Tensile strength

The following approaches were helpful in the formulation of PVP-VA64 based ASD tablets•Mannitol as a filler, used in a ratio with MCC•
Ac-di-sol as the disintegrating agent at a ~10% loading•
Inclusion of formulation additives such as inorganic salts
We also found that modifying the following was beneficial•
Filler type (Mannitol vs Dicalcium Phosphate)•Ratio of MCC: Filler•% Intragranular loading

SampleLot #40:60 Z160:PVP-VA64 ASD
40:60 Z160:PVP-VA64 125mg Tablet 100 MPa - F440:60 Z160:PVP-VA64 125mg Tablet 100 MPa - F540:60 Z160:PVP-VA64 125mg Tablet 100 MPa - F740:60 Z160:PVP-VA64 125mg Tablet 100 MPa - F13
40:60 Z160:PVP-VA64 125mg Tablet 100 MPa - F1440:60 Z160:PVP-VA64 125mg Tablet 100 MPa - F15

A4-976-71
A4-976-90-F4
A4-976-90-F5
A4-976-90-F7
A4-976-90-F13
A4-976-90-F14
A4-976-90-F15

Total Drug
CmaxGB(µgA/mL)
2182562426353315
52

Total DrugCmaxFaSSIF(µgA/mL)
85.6
110.4
105.1
30.8
23.1
130.8
27.0

Total Drug
Total Drug
Disintegratio
AUC 35-210 FaSSIF
C210
n time (min)(min*µgA/mL) (µgA/mL)
NA
9400
26.8~311200
41.8~2011300
48.9
>210
3800
0.0
>210
3000
0.0~312800
49.1>2104200
18.1