AAPS-2012 Research Presentations Pharmaceutical Development US

Boehringer-Ingelheim Pharmaceuticals

AAPS Annual Meeting and Exposition October 14-18, 2012, McCormick Place, Chicago

Optimization of Freeze-dried Nanosuspension and its Application for IV

infusion

Imaging of Slow Releasing API-PVP Amorphous Solid Dispersion Tablets

Rotating Disk Dissolution to Understand and Predict Bioperformance Michael Hawley, Pharmaceutical Development US This presentation discusses the use of the rotating disk dissolution (intrinsic dissolution) technique during development to understand dissolution mechanisms and to assist in the prediction of oral bioperformance. Rotating disk dissolution is a very simple, fundamental measurement method which can be used to characterize API dissolution both qualitatively and quantitatively. In its most straightforward application, the rotating disk dissolution rate can be shown to be proportional to bioavailability. Its more powerful use is in understanding dissolution mechanisms and designing formulations through awareness of what is happening in the diffusion layer. Knowledge of the impact of solid form transformations and different mechanisms for precipitation on the rotating disk dissolution rate are critical to formulation design. Using these facts, examples are shown which take advantage of the properties of individual molecules to enhance bioperformance of formulations. In summary, rotating disk dissolution is a far reaching technique which can be successfully applied to the problem of understanding and predicting bioperformance.

CBZ Summary

Because Form I converts to the hydrate most rapidly, it is actually less bioavailable than Form III, which is less soluble, but does not convert to the hydrate

Solid form conversion is important to bioavailability for carbamazepine solid forms

Carino et al., Relative Bioavailability Estimation of Carbamazepine Crystal Forms using an Artificial Stomach-Duodenum

Model. J Pharm Sci 95:116-125, 2006

2

4

6

8

10

12

14

0.2 0.4 0.6 0.8 1

Do

g A

UC

(ugh

/mL)

RDD Concentration at 60min (mg/mL)

How Can We Reformulate?

•One approach - Diffusion layer modulation

•Only impacts the diffusion layer, not the bulk fluid

Tota

l C

oncentr

ation o

f B

ase

Diffusion Layer pH

Free Base Solubility

Salt SolubilityAB

Depressed Salt Solubility

DLpHM

C

DLKspM

Supersaturation Ratio

Equilibrium Solubility

Other Solubility

Figure 5: Schematic depiction of how a diffusion layer modulated solid can impact

relative supersaturation ratios and therefore precipitation rates. Examples of pH

modulation and Ksp modulation in the diffusion layer are described in the text.

RDD of DLM solid (API + citric acid) (2:1)

•pH 4 dissolution

0 5 10 15 20

0

5

10

15

20

Concentr

ation (mg/m

L)

Time (min)

DLpHM Solid

API Only

Dog Study Results

Diffusion layer pH modulation works (~4x enhancement)PNU-243672A

-0.05

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0.45

0.5

0 10 20 30

Time (hr)

Pla

sm

a C

on

c (

nM

/mL

)

pH modified

Salt Suspension

RDD Summary

RDD is a simple but powerful tool

• Useful for solid form selection

• Identify forms that dissolve well

• Understand the fundamentals behind formulation performance

Importance of RDD shape

• Phase transformations These are identified by non-linear profiles Solid form of pellets can be easily identified

Understanding dissolution

• Diffusion layer conditions can be easily modified in RDD

• RDD can be used to develop better solid forms and formulations

Unleashing the Potential of New Excipients: A Way Forward ( excerpt from presentation by Dr K. Horspool (Thurs 18th Oct) in the symposium “ New Excipients: Unmet Needs, Development and Regulatory Challenges”

•Define a forum for collaborative development of new materials – pharma and excipient developers. High level objectives:

•Work together to influence agencies in accelerated independent approval of excipients

•Support existing materials of interest – share non-propriety information to build data set (non clinical safety, clinical safety)

•Jointly define “targets of value” to direct future new material design and development

•Create a shared de-risked portfolio of materials or technologies with open access to partners