A New Approach to Accelerated Drug-Excipient Compatibility Testing

A New Approach to Accelerated Drug-Excipient Compatibility Testing

Jonathan L. Sims,* Judith A. Carreira, Daniel J. Carrier, Simon R. Crabtree,

Lynne Easton, Stephen A. Hancock, and Carol E. Simcox

GlaxoSmithKline R & D, New Frontiers Science Park, Harlow, Essex, UK

ABSTRACT

The purpose of this study was to develop a method of qualitatively predicting the most likely

degradants in a formulation or probing specific drug-excipient interactions in a significantly

shorter time frame than the typical 1 month storage testing. In the example studied,

accelerated storage testing of a solid dosage form at 508C, the drug substance SB-243213-A

degraded via the formation of two oxidative impurities. These impurities reached a level of

1% PAR after 3 months. Various stressing methods were examined to try to recreate this

degradation and in doing so provide a practical and reliable method capable of predicting

drug-excipient interactions. The technique developed was able to mimic the 1-month’s

accelerated degradation in just 1 hr. The method was suitable for automated analysis, capable

of multisample stressing, and ideal for use in drug-excipient compatibility screening.

Key Words: Drug-excipient interactions; Degradation studies; Automation; Prediction of

impurities.

INTRODUCTION

During the preparation and storage of drug products,

new impurities often form as a result of an interaction

between the drug substance and species introduced by

formulation.[1 – 3] Inextremecases, thiscanleadtoshelf life

issues which necessitate reformulation. The current

International Conference on Harmonisation (ICH) guide-

line; Stability Testing of New Drugs and Products,

Q1A(R)[4] requires stress testing of drug substance

to help establish the likely degradation pathways.

Typically, degradation processes are studied for both the

drug substance and drug product using extremes of pH,

heat, light, and oxidizing agents.[5 – 7] These experiments

are also used to develop stability indicating impurities

methods for the drug substance and drug product.[8 – 10]

However, many of the degradation products observed in

these processes do not occur in the drug substance or

product when stored under normal conditions and are not

observedinthestability trials.Thepresenceofunnecessary

impurities in stressed samples can cause the development

of overly complicated methods leading to problems in

119

DOI: 10.1081/PDT-120018476 1083-7450 (Print); 1097-9867 (Online)

Copyright q 2003 by Marcel Dekker, Inc. www.dekker.com

*Correspondence: Jonathan L. Sims, GlaxoSmithKline R & D, New Frontiers Science Park, Third Avenue, Harlow, Essex,

CM19 5AW, UK; Fax: 01279 622380; E-mail: [email protected].

PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY

Vol. 8, No. 2, pp. 119–126, 2003

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016

©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.

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the analytical supportof late-stageproducts.Therefore, we

set out to develop a procedure that would enable us to focus

on the most likely degradants to arise from a given tablet

formulation by applying stressing techniques to the

solid state.

The formulation of a drug substance involves it being

blended with a combination of different excipients to

maximize the products ability to administer the dosage

effectively. Ideally, the excipients used in the formulation

should not interact with the drug substance or introduce

species capable of accelerating the formation of new

impurities. Certain classes of compounds are known to be

incompatible with given excipients[11]; thus, knowledge of

the chemistry of the drug substance can often minimize

formulation surprises. Heat and water are the primary

source of drug product incompatibilities and play a critical

role in the stability of a drug substance to degradation.[12]

Many different degradation mechanisms exist but those

mediated by surface moisture appear to be the most

common,[13] and as a result, it is important that stressing

methods incorporate water to allow for the formation of all

possible impurities. The way in which water facilitates

degradation is not fully understood, but the work carried

out by Kontny et al.[13] has confirmed its importance.

Degradation problems can, therefore, be difficult to avoid

because water is often trapped inside drug products on

formulation. Many excipients are hygroscopic

materials[14,15] and absorb water during formulation

processes such as wet granulation. Excipients generally

contain more free moisture than the drug substance,[14] and

in an attempt to obtain the most thermodynamically stable

state, water is able to equilibrate between the tablet

components.[16] Formulation can, therefore, potentially

expose the drug substance to higher levels of moisture than

normal, which greatly increases the susceptibility of even

the most stable compound to degradation. Another

commonsourceof formulationproblemsis the interactions

that can occur between residues found inexcipients and the

drug substance.[3] Excipients are often isolated from

natural products or polymerization processes and may

contain low-level process impurities, particularly in the

case of polymeric excipients such as the polyethylene

glycols. These residues have the potential to react with the

drug substance; therefore, it is important to know the purity

and composition of the excipient prior to formulation.

These incompatibilities are often difficult to predict but

represent a very real source of formulation instability.

Thermal techniques are a rapid tool that can be used

to examine for incompatibilities between a drug substance

and excipients.[17,18] Differential scanning calorimetry

(DSC) is currently the leading technique in this field. The

main benefit of DSC over stressed storage methods is its

ability to quickly screen potential excipients for

incompatibilities, although other features such as low

sample consumption make it an attractive method.

Although DSC is unquestionably a valuable technique,

interpretation of the data is not without problems.

Similarly, isothermal microcalorimetry is becoming

popular as a method of detecting changes in the solid

state of drug-excipient mixtures through heat changes.[19]

The results from these methods can be indicative of

whether formulations are stable, but thermal techniques

reveal no information concerning the cause or nature of

any incompatibility. Techniques such as hot stage

microscopy and scanning electron microscopy can be

used in conjunction with DSC to determine the nature of

an apparent incompatibility.[20] These techniques study

the morphology of the drug substance and can determine

the nature of physical transformations, thus indicating the

type of incompatibility that has occurred.

MATERIALS AND METHODS

Manufacture of Tablets

Tablets were manufactured by using a wet granula-

tion process. The active, povidone, sodium lauryl sulfate

and microcrystalline cellulose were granulated with

water. Further microcrystalline cellulose, croscarmellose

sodium, and magnesium stearate were added extragra-

nularly, and the mixture was compressed into tablets.

Tablets were then coated in a fluid bed dryer.

Drug-Excipient Mixtures

The basic formulation contains active plus micro-

crystalline cellulose, crosscarmellose sodium, povidone,

magnesium stearate, sodium lauryl sulphate, titanium

dioxide, hydroxypropyl methylcellulose, and polyethy-

lene glycol 400. Experiments where the drug substance

was stressed with either single or binary excipient

Figure 1. Structure of SB-243213-A.

Sims et al.120



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mixtures used 10 mg of each material. All mixtures

prepared from dry powders were ground together by

using a pestle and mortar.

Tablet Stability Studies

Tablets were stored in high-density polyethylene

bottles with heat induction foil seals at 508C, 408C/75%

relative humidity, 258C/60% relative humidity and 58C.

HPLC Method

HPLC analysis was performed by using a 5-mm,

150 £ 3.9 mm i.d. symmetry C18 column (Waters, Herts,

UK) at 408C with a mobile phase flow rate of 1 mL/min.

The gradient elution used acetonitrile and a 50 mM

ammonium formate buffer adjusted to pH 3.3 with formic

acid. The initial mobile phase composition of 25%

acetonitrile was increased to 60% linearly over 25 min,

followed by an increase to the final composition of 80%

linearly over 5 min and held at this composition for 5 min.

Degradants were routinely monitored by using a UV

detector at a wavelength of 266 nm with identity

confirmed by using mass spectral detection. The sample

and controls were dissolved in a 50/50 vol/vol mixture of

water and HPLC grade acetonitrile and were passed

through a 0.2mm filter to remove any undissolved

excipients.

SK233/STEM Automated Analysis System

This instrument consists of an Anachem SK233 XL

autosampler with 183-mm piercing probe, Gilson 402

Figure 2. Original stressed tablet impurity profile.

Figure 3. Structures of impurities.

Drug-Excipient Compatibility Testing 121



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dilutor, and STEM Corporation model RS1000 reacto

station controlled by SK233 Workstatione software

(Anachem, Luton, Beds., UK) coupled to an Agilent

1100 high-pressure gradient HPLC system with diode

array UV detection (DAD) and electrospray ionization

mass spectrometric detection (MSD) controlled by

Agilent Chemstation software version Rev A7.01

(Agilent Technologies, California, USA).

RESULTS AND DISCUSSION

Theseriesofexperimentsdescribedinthisarticlewere

designed to try and recreate the degradation observed

following the 3-month storage at 508C of the initial clinical

formulation for SB-243213-A, a 5HT2c receptor antagon-

ist under development for the treatment of anxiety and

depression (Fig. 1). Figure 2 shows a comparison of the

impurity profiles for the degraded product, drug substance

control, placebo, and blank; the degradation produces two

impurities at a level of approximately 1% PAR designated

as impurity A and impurity B (Fig. 3). The structures of

these impurities had been elucidated previously during

forced degradation experiments on batches of drug

substance, and the major degradation products are shown

in Fig. 4. However, impurities A and B are only detected as

major components when SB-243213-A is stressed with

light and oxidizing agents, not from heat and moisture

stressing.

The drug-excipient compatibility testing method

adopted by Serajuddin et al.[21] involved the storage of

formulated samples with 20% vol/wt added water at

508C for 1–3 weeks. We desired a more rapid screening

system; therefore, samples were prepared with 20%

vol/wt of water, placed in closed vials, and stored in an

Figure 4. Degradation of SB-243213-A.

Figure 5. Glass weighing boat in vial for oven experiments.

Sims et al.122



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oven at 1008C for 1 and 3 days, with relevant controls.

The results from the oven experiments revealed that

although the desired degradants were being generated,

the major degradation process differed from that seen in

the original study to such an extent that impurities A and

B would have been considered insignificant. It is of

interest that the drug-excipient sample stressed in the

presence of water formed impurities A and B at increased

levels in comparison with the same sample stressed

without water. This confirmed the importance of water as

a promoter of the observed degradation process.

Following the results obtained from the solid-state

oven experiments, we decided to modify the experimen-

tal design to produce a more controlled and humid

atmosphere on the basis that stressing the sample in the

presence of moisture rather than having the sample in

direct contact with water might provide a more predictive

result. The method required the sample to be held in

a glass weighing boat inside a closed vial with water

around the outside of the boat (Fig. 5). The initial

experiment stressed the sample for 24 hr at 1008C, and

this resulted in the formation of the oxidative impurities

at low levels (A and B forming at 0.08% and 0.67% PAR,

respectively), alongside the major degradation products

observed in the previous heating experiment. The level of

degradation found, in comparison with the stored drug

product, was considerable and significantly different

from that shown in Fig. 2. The experiment was repeated

by using a stressing time of 1 hr, and the overall

degradation was reduced. Furthermore, it was believed

that 1008C might be too high a temperature to mimic

the drug product result, and a comparison was performed

at temperatures of 60, 80, and 1008C using three

subsamples from a single preparation of the formulation.

At 1008C, a large number of degradants not found in the

drug product predominated, whereas in the 60–808C

range, the oxidative impurities were the predominant

result (Fig. 6). To evaluate the reproducibility of the

system, a drug-excipient mixture was prepared, and three

subsamples were stressed at 808C for 1 hr. The degradants

Figure 6. Oven experiment results.

Figure 7. STEM Block with condenser array.

Table 1. Reproducibility of stressing in oven.

Impurity A %PAR Impurity B %PAR

Sample 1 0.33 0.36

Sample 2 0.29 0.24

Sample 3 0.29 0.23




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found for the three samples gave good agreement,

confirming the method to be reliable; the results are

summarized in Table 1.

We had previously successfully automated solution

stressing of drug substance by adapting the approach of

Armitage et al.[22] using the SK-233 and STEM

system,[23] which has 10 reaction tubes with condensers

(Fig. 7). This equipment was, therefore, used to try to

develop a method capable of on-line stressing and

analysis for solids. The drug and excipients were

prepared as described earlier and were stressed in the

standard STEM tubes with 20% vol/wt added water at

808C. The STEM results (Fig. 8) were very similar to

those obtained for the oven solid-state experiments.

These results confirmed that keeping the sample and

water separate is a necessity for a predictive method;

therefore, we designed and built a novel reaction vial

(Fig. 9) for the STEM block system. The new vial is only

5 cm at the shoulder (equivalent to the depth of the hole

in the STEM block) and, therefore, only the cap

protrudes above the heated block. It has the sample in an

insert inside the vessel, water is contained around the

outside of the insert, and the vial sits in the stem block.

Samples of the formulation and drug substance were

heated in this apparatus at 808C for 1 hr. For the

formulation, this experiment generated impurities A and

B at a level of 0.36% and 0.53% PAR, respectively,

giving a result consistent with that found in the original

storage study (Fig. 10). In the STEM reactor, the drug

substance can also be seen to undergo the same

degradation process as the formulation although to a

lesser extent. As in the oven experiments, we performed

a reproducibility study for the STEM vial using four

subsamples from a prepared mixture which produced

Figure 8. Chromatograms from standard STEM stressing experiments.

Figure 9. Reaction vessel.

Sims et al.124



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results consistent with the impurities A and B being the

most significant degradants for this formulation (Table 2).

The experiments described in this article prove the

viability of performing rapid stressing experiments on

drug products; however, the exposure time may vary

dramatically depending on the nature of the drug

substance. SB-243213-A is reasonably easy to degrade,

hence, the optimum stressing time of 1 hr. Other

formulations of SB-243213-A could be stabilized by the

excipient combination[12] and require longer exposure;

therefore, we do not believe that a generic method can be

proposed for this application. Because the STEM block

has a capacity of 10 vials, it is possible to have samples

taken at different time points to establish the optimum

exposure time; clearly, if the required exposure is in the

order of weeks, then there is no need to automate.

The STEM block plus 10 vials is relatively

inexpensive as a stand-alone option and can be used for

screening of different formulations for variation in

degradation or for the potential to stabilize a given

formulation through selected additives.[12] With 10 vials

exposed to identical heating, the apparatus is suited to

structured experiments exploring binary or tertiary

mixtures to identify specific degradation drivers.[21] The

vial design is also suitable for stressing of whole tablets.

CONCLUSION

A forcing method has been developed, which is

capable of reproducibly producing degradants in a

formulated product which were previously revealed

during a formal accelerated stressing study. The new

method offers a significant reduction in the time taken to

discover the most likely degradants for a formulation and

can also be applied to comparative studies of potential

formulations.

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A New Approach to Accelerated Drug-Excipient Compatibility Testing