Supporting Information

A Case Study: Using DOE to Achieve Reliable Drug

Administration

Sven Sjövall,* Lars Hansen and Bo Granquist

1
TYPICAL RELEASE TEST RESULTS

Compound 2

Parameter Specification Result

Appearance White powder Complies

Identification by IR The spectrum should be in Complies

agreement with that of a
corresponding preparation of the
current reference material

Identification by UV The spectrum should be in Complies

agreement with that of a
corresponding preparation of the
current reference material

Assay by UV-absorption 97.0 – 102.0 % 99.1 %

HPLC purity test Any single impurity: ≤ 0.5% < 0.5%

Sum of impurities: ≤ 1.5% < 1.5%

Compound 3

Parameter Specification Result

Appearance White powder Complies
Identification by IR The spectrum should be in Complies
agreement with that of a
corresponding preparation of the
current reference material

Identification by UV The spectrum should be in Complies

agreement with that of a
corresponding preparation of the
current reference material

Assay by UV-absorption 97.0 – 102.0 % 97.8 %

HPLC purity test Any single impurity: ≤ 0.5% < 0.1%

Sum of impurities: ≤ 1.5% < 0.1%

2
Compound 4

Parameter Specification Result

Appearance White powder Complies

Identification by IR The spectrum should be in Complies

agreement with that of a
corresponding preparation of the
current reference material

Identification by UV The spectrum should be in Complies

agreement with that of a
corresponding preparation of the
current reference material

HPLC purity test Any single impurity: ≤ 0.5% < 0.5%

Sum of impurities: ≤ 1.0% < 0.2%

N-methyl aniline by HPLC ≤ 0.1% < 0.1%

Toluene by HPLC ≤ 0.1% < 0.1%

Heavy metals ≤ 20 ppm < 20 ppm

Free chloride ≤ 0.05% < 0.05%

Water content (USP <921>, ≤ 1.0% < 0.1%

current ed.)

Sulfated ash (EP 2.4.14, current ≤ 0.1% < 0.1%

ed.)

Assay by HPLC 98.0 – 102.0 % 99.8

Microbiological quality ≤ 10 org/g < 10 org/g

3
PROTON NMR

Proton NMR spectra were recorded on a Bruker 250 MHz spectrometer in CDCl3. Chemical shifts are

reported in parts per million downfield from tetratmethylsilane.

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H NMR (3): δ 15.6 (s, 1H, COOH), 14.6 (s, 1H, OH), 8.3 (m, 1H, Ar), 7.8 (m, 1H, Ar), 7.5 (m, 2H,

Ar), 3.7 (s, 3H, NCH3).

1
H NMR (4): δ 12.4 (broad s, 1H, OH), 8.1 (m, 1H, Ar), 7.5 (m, 1H, Ar), 7.1 (m, 7H, Ar), 3.5 (s, 3H,

NCH3), 3.3 5 (s, 3H, NCH3).

DOE RAW DATA

variables response

exp X1 X2 X3 dissolution60 min (%)

1 20 15 6 66.7

2 30 15 6 87.6

3 20 30 6 83.4

4 30 30 6 93.4

5 20 15 11 63.0

6 30 15 11 93.7

7 20 30 11 70.3

8 30 30 11 88.6

9 28 15 8.5 88.8

10 28 15 8.5 86.5

11 28 15 8.5 89.7