1) A study was conducted to reverse engineer an oral suspension containing a poorly water soluble drug to match the dissolution profile of the reference listed drug (RLD) using quality by design principles. 2) Two multivariate design of experiments (DoEs) were used, along with live in-situ dissolution monitoring using fiber optic probes, to identify formulation factors influencing dissolution and reduce development time. 3) The approach resulted in a new formulation matching the RLD dissolution profile within 72 hours, much faster than traditional methods requiring costly and time-consuming HPLC analysis.

1. RESEARCH POSTER PRESENTATION DESIGN © 2015
www.PosterPresentations.com
Quality by design (QbD) is strategically crucial to implement early in formulation development to
achieve superior product performance (1). To maintain aggressive timelines one factor at a time
(OFAT) has been superseded by multivariate Design of Experiments (DoE) (2). DoE is a
powerful tool that identifies first and second order interactions within the design space. Although
DoE reduces experimentation required as compared to OFAT analytical analysis becomes the rate
limiting step. Technological advancements must be co-employed with DoE to reduce total
development time. This study demonstrates the coupling of 2 multivariate DoEs with live in-situ
dissolution monitoring by fiber optic (FO) probes resulting in reduced development time. Herein
an oral suspension containing a poorly water soluble API (BCS Class IV) underwent reverse
engineering to match the RLD dissolution profile. Pre and post formulation multivariate DoE
analysis was used to match the dissolution profile of the reference listed drug (RLD) per USP
parameters.
Abstract
Dissolution media: 10% 0.1M Sodium Methoxide/H2O 900mL.
Dissolution: Vankel Dissolution Bath (VK700)- Dissolution bath with apparatus 2, vessel
temperature 37°C, RPM 50 , run time 2 hrs.
PION Rainbow®: In situ fiber optic probes with dedicated PDA (200-720 nm) for each channel
with 2 mm stainless steel probes, sampled every 5 min for 2 hrs. Representative set up is shown in
Figure 1.
Microfluidizer LM10: Pre-processing DoE formulations were individually micro-fluidized
suspensions and diluted in stock vehicle. Post-processing DoE formulations were prepared by
microfluidizing a stock suspension and aliquoted to individually prepared vehicles.
Minitab®: Statistical processing software.
Reagents: Poloxamer 188 BASF (Greenville OH), simethicone emulsion (Dow Corning Midland
MI), xanthan gum (Vanderbilt Minerals Norwalk CT).
Simulated Intestinal Fluid (SIF): Sodium Taurocholate (Spectrum Chemical New Brunswick NJ) ,
Lecithin (TCI Cambridge MA), NaOH (Amresco Solon OH), Sodium Phosphate Monobasic (J.T.
Baker Phillipsburg, NJ), Sodium Chloride (Spectrum Chemical New Brunswick NJ), DI H2O.
Simulated gastric fluid (SGF): Sodium Laurel Sulfate (Spectrum Chemical New Brunswick NJ),
Sodium Chloride (Spectrum Chemical New Brunswick NJ), 12M HCl (J.T. Baker Phillipsburg,
NJ), DI H2O.
Methods
Results Continued
Conclusions
Statistical analysis for the 2 DoE experiments, provided main effects of CQAs which directly
affected the dissolution profile. Through regression analysis an equation was obtained and a
second prototype (16002) was prepared which showed a good match to the RLD dissolution
profile, Figure 7. An additional batch (16003) was manufactured and confirms RLD match in
SGF and SIF, Figure 7 a&b. The Pion Rainbow fiber optic dissolution monitoring system showed
parity with USP testing by HPLC, Figure 6. The use of PION allowed the collection of more data
than possible by HPLC while eliminated costly solvent usage and analyst time. The entire
project was completed in 72 hours with Pion in-situ fiber optic probes. This would not be
possible with traditional HPLC methods.
References
1.Yu, L.X. et al. AAPS 2014, 16, (4), 771-783.
2.Weissman S.A., Anderson, N.G. Org Process Res. Dev. 2015, 19, (11), 1605-1633.
1CoreRx , Clearwater, Florida, 33710, United States of America;
Travis.Webb@corerxpharma.com
T.Webb1, M. Favero1, J. Maxwell1, B. Hilker1, and J. Cacace1
Multivariate DoE & Live in-situ Dissolution Monitoring: Strategy for Reverse Engineering Success.
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%D
Time (min)
DISSOLUTION PROFILE
RLD
16001 (Pre-DOE)
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Time (minutes)
DISSOLUTION PROFILE HPLC VERIFICATION
RLD Pion
16002 Pion
16002 HPLC
HPLC Samples (N)/sample Run Time Hours
ASSAY 20 1 7 2.33
DISSO 20 6 30 60
Results
Initial prototype: Using common reference sources such as: FDA Inactive Ingredient Guideline
(IIG) Database, patent information, and drug label insert an initial generic prototype was
manufactured. The prototype (16001) dissolution profile was compared to the reference listed
drug (RLD), Figure 2. 16001 showed slower release compared to RLD.
Figure 2. Initial generic prototype 16001 (pre-DOE) vs. RLD
DOE & Critical Quality Attributes (CQA): A review of formulation parameters and materials
identified xanthan gum and poloxamer as CQAs for “pre-processing”. While xanthan gum,
poloxamer , and simethicone are CQAs for “post-processing”. Employed Minitab® 2 full
factorial with center point and main effects consistency index (CI) plot pre-processing are shown
in Figures 3 a&b respectively.
PION
Rainbow FO
Probe
Figure 1. Pion FO probe in dissolution bath
DOE full factorial run results: Figure 5 pre-processing DOE results shows the plotted rheology
results of 2 full factorial and center point formulations compared to the RLD. Figure 6 post-
processing DOE results provides the in-situ Pion FO dissolution results for 3 full factorial and
center point formulations compared to the RLD.
Figure 5. Pre-processing 2 full factorial with center point results
Figure 6. Post-processing 3 full factorial with center point results
Minitab DOE Finalization: Results obtained for the 2 DOE factorials, shown above, were
processed in Minitab® and the design space was mapped. From the Minitab® design space
analysis a new formulation was identified and manufactured (16002 “After DOE”). The
dissolution profile was obtained and compared to the RLD and 16001 “Before DOE” formulations
using Pion Rainbow, Figure 7.
Figure 7. Dissolution profile comparisons , before DOE, after DOE, and RLD.
Results Continued
USP Compendial Testing Verification: Pion Rainbow FO dissolution data was then compared to
USP dissolution testing via HPLC. Figure 8 shows the comparison of Pion Rainbow in-situ FO
probe and USP dissolution testing by HPLC.
Figure 8. HPLC backend comparison to Pion Rainbow dissolution profile.
Formulation robustness: To ensure the formulation obtained was indeed similar to the RLD an
addition batch was manufactured per Minitab DOE results (16003). Dissolution profiles of 16003
and the RLD were compared using SGF and SIF media. Figures 9 a&b show RLD versus 16003
in SIF and SGF respectively.
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Time (min)
DISSOLUTION SGF
16003
RLD
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Time (min)
DISSOLUTION SIF
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RLD
Figure 9. (a) Simulated gastric fluid (b) simulated intestinal fluid dissolution profile comparisons with PION Rainbow.
(7a)
(7b)
Time Savings: Utilizing novel technology, the PION rainbow eliminated the need for costly and
time consuming HPLC backend work. Table 1 shows estimated runs times for the USP HPLC
methods. The initial work saved over 60+ hours of physical HPLC pumping time.
Table 1. USP HPLC run time saved by using PION Rainbow which removes HPLC back end.
Presenter: Sr. Formulator
Travis.Webb@corerxpharma.com
727-259-6950
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SHEARRATE(1/S)
VISCOSITY (CP)
PRE-PROCESSING RHEOLOGY
Formulation 1
Formulation 2
Formulation 3
Formulation 4
Formulation 5
RLD
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TIME (MIN)
POST-PROCESSING DISSOLUTON PROFILE
Form 1
Form 2
Form 5
Form 6
Form 7
Form 8
Form 9
RLD
(POST PROCESSING )Final Formulation Composition
StdOrder RunOrder CenterPt Blocks Xanthan Gum Poloxamer Simethicone
2 1 1 1 1.30 1.0 0.00
5 2 1 1 0.80 1.0 0.50
8 3 1 1 1.30 2.0 0.50
3 4 1 1 0.80 2.0 0.00
7 5 1 1 0.80 2.0 0.50
1 6 1 1 0.80 1.0 0.00
4 7 1 1 1.30 2.0 0.00
9 8 0 1 1.05 1.5 0.25
6 9 1 1 1.30 1.0 0.50
Responses Acceptable Range
% dissolution at 30 minutes Maximize
% dissolution at 60 minutes Match RLD
Viscosity at 0 Shear Define Design Space
1.301.050.80
70
65
60
55
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40
2.01.51.0 0.500.250.00
Xanthan Gum
Meanof30minDisso
Poloxamer Simethicone
Corner
Center
Point Type
Main Effects Plot for 30 min Disso
Fitted Means
(Pre-Processing) Pre Microfluidization Composition
StdOrder RunOrder CenterPt Blocks Xanthan gum Poloxamer
4 1 1 1 0.00 0.2
2 2 1 1 0.00 1.0
1 3 1 1 0.04 0.2
3 4 1 1 0.04 1.0
5 5 0 1 0.02 0.6
Responses Acceptable Range
% dissolution at 30 minutes Maximize
% dissolution at 60 minutes Match RLD
Viscosity at 0 Shear Define Design Space 0.040.020.00
8000
7500
7000
6500
6000
1.00.60.2
Xanthan gum
MeanofCI
Poloxamer
Corner
Center
Point Type
Main Effects Plot for CI
Fitted Means
Minitab Post-processing 3 full factorial with center point and post-processing main effects
plots from 30 and 60 minute dissolution are shown in Figures 4 a, b, and c respectively.
Figure 3a. Pre-processing full factorial with center point Figure 3b. Main effects plot pre-processing.
1.301.050.80
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2.01.51.0 0.500.250.00
Xanthan Gum
Meanof60mindisso
Poloxamer Simethicone
Corner
Center
Point Type
Main Effects Plot for 60 min disso
Fitted Means
Figure 4b. Main effects dissolution 30 min.
Figure 4a. Pre-processing full factorial with center point
Figure 4c. Main effects dissolution 60 min.
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Time (Min)
DISSOLUTION PROFILE
RLD
After DOE (16002)
Before DOE (16001)