Division of Pharmaceutical Analysis

Research in support of the Critical Path Dimensions

•Ensuring Safety

•Demonstrating Medical Utility

•Industrialization Process

Lucinda F. Buhse, Ph.D., Director

Division of Pharmaceutical AnalysisCritical Path Initiatives

• Characterize Novel Dosage Forms/ Complex Drug Substances

• Measurement and ID of Micro and Nanoparticles

• Establish Appropriate Surrogate Measurements Techniques

• Drug Authenticity and Anti-counterfeiting Techniques

• Process Analytical Technologies for Manufacturing

• Computational Chemistry (Chemometrics)

Characterization of Novel Dosage Forms/ Complex Drug Substances

Examples:• Liposomes –characterization after chemical and physical

changes• Transdermals – physical characterization of adhesive strength• Conjugated Estrogens – improvement of LCMS comparison

method• Protein Products -Detection of Aggregation and Degradation

Regulatory Accomplishments:• Input into Conjugated Estrogens Guidance

Monitoring Liposomal Drug Products (LDPs) Under Manufacturing Stress Conditions

• LDPs (PEGylated Doxil ®, Conventional DaunoXome®)

• Stress Conditions–Thermal–Oxidative–Acid and Base–Light–Sonication–Detergent

• Analytical methods for Monitoring quality– Drug Substance (HPLC-UV)– Encapsulation Efficiency (fluorescence)– Lipid Composition (HPLC-ELS)– Particle Size– Zeta Potential

Transdermal Drug Delivery Systems: Adhesive StrengthSeveral sizes of patches, types of drug delivery, application periods, and shapes.

Example of drug-in-adhesive Example of reservoir

Test method development variables and constants:Test panel Rolls Rolling time Test panel cleaning

Angle of pull Pull speed Dwell time Environment

Size NameType

(Drug-In-Adhesive; Reservoir) Application period Shape

3.5 cm2 CATAPRES-TTS-1 Reservoir 1 time/ week square

9.375 cm2 CLIMARA Drug-In-Adhesive 1 time/ week octagon

22.0 cm2 VIVELLE Drug-In-Adhesive 2 times/ week oval

2.5 cm2 VIVELLE-DOT Drug-In-Adhesive 2 times/ week rectangular

40 cm2 DURAGESIC Reservoir 72 hours rectangular

2.5 cm2 TRANSDERM SCOP Reservoir 3 days circular

Measurement and ID of Micro and Nanoparticles

Examples:

• Sunscreens – evaluation of particle size in the formulation

• Nasal Sprays

– evaluation of Raman Microimaging for particle sizing of active pharmaceutical ingredient

– evaluation of Andersen Cascade Impactor configuration for use in assessing the distribution of fine particles

Regulatory Accomplishments:

• Input into Nasal Spray BA/BE Guidance• Development of compendial method for cyclosporine particle

size

Measuring API Particle Size in the Presence of Particulate ExcipientsRaman Chemical Imaging Of Aqueous Nasal Spray SuspensionRegion of Interest2

Raman Shift (cm-1)

Arb

itrar

y In

tens

ity

1630 1640 1650 1660 1670 1680 1690 1700

Brightfield Reflectance Image Polarized Light Image

10m

Normalized Imaging Spectrometer Raman Spectra Brightfield / Raman Image Overlay

Drug Peak

Raman Chemical Image of BDP

Figure 7. BDP Aqueous Nasal Spray Suspension – ROI 2

Establishment of Appropriate Surrogate Measurement Techniques

Example:• Mefloquine HCl – evaluation of polymorphs of API with respect

to BA of finished dosage form• Megestrol Acetate – evaluation of dissolution media to detect

BE/BA differences• Evaluation of variability in Dissolution testing – search for an

alternative technique to establish BE/BA

Regulatory Accomplishments:• Input into resolution of prophylaxis failure of military use product• Input into resolution of generic manufacturer equivalency

challenge

Dissolution: Less variability is needed

• The current USP 10-mg Prednisone Calibrator Tablets exhibit slower dissolution over time

• Acceptance limits are so large, that improper mechanical calibration may not be detected

• Differences in product testing can often be traced to improper mechanical calibration and/or degassing

Lot Date Mean (n=6)

SD (%)

USP Limit (%)

M 4/00 34.8 2.2 28-42

M 10/00 28.9 0.9 28-42

N 12/01 35.7 1.6 28-54

N 11/02 35.4 1.4 28-54

N 6/03 28.0 0.7 28-54DPA/FDA Data using Apparatus 2; data from only one apparatus shown. Note the USP adjusts the

limits of each new lot of calibration tablets to reflect the anticipated decrease in dissolution.

Example:

• Assessment of technologies for detection of counterfeit (IRMS, NIR, TGA, Terahertz)

Regulatory Accomplishments:

• Quality of foreign Active Pharmaceutical Ingredients program

• Foreign Internet Sample Studies

Drug Authenticity and Anti-counterfeiting

Techniques

IRMS- Isotope Ratio Mass Spectrometry

Naproxen: d13C vs d18O

-34

-32

-30

-28

-26

-24

-5 0 5 10 15 20

d18O (‰ vs VSMOW)

d13C

(‰

vs

VP

DB

)

India,Mfr A

Ireland,Mfr E

Italy,Mfr C

India,Mfr B

USA, Mfr F

Italy,Mfr D

IRMS can provide the source of active pharmaceutical ingredients (APIs). In the bivariate isotope ratio graph shown, the typical clustering of the data is consistent with manufacturer-based isotopic provenance.

Process Analytical Technologies for Manufacturing

Examples:

• Assessment of technologies for PAT (Terahertz, NIR)

• Effect of coating composition and thickness on PAT measurements

• Effect of excipient and excipient/drug interaction

Terahertz Spectrometry

Partial Least Squares Fit

Content (mg) by NIR PLS Calibration from HPLC

TH

z P

red

icte

d C

on

ten

t (m

g)

Ab

sorb

an

ce

Energy (5 - 45cm-1)

Terahertz Absorption Spectra

Acetaminophen tablet content: 65 – 135 mg scanned by NIR and Terahertz Absorbance.

Non-Destructive and Penetrating • Imaging of Biological Tissue• On-Line or At-Line Quality Control

including whole tablet imaging

Computational Chemistry (Chemometrics)

Examples:• Understanding chemometric software packages• Understanding limitations and benefits of multivariate

techniques

Critical Path - Chemometrics

Near Infrared Reflectance and Transmittance of formulated tablets

Multivariate models in PAT – Partial Least Squares (PLS) analysis

Uncoated Acetaminophen tablets in 9 dosage levels 65 – 135mg.Tablet Reflectance – full range

PLS – Mean Centered, 2nd Derivative, 3 Factors

Tablet Transmittance – limited spectral range

PLS – Mean Centered, Direct Spectra, 3 Factors

Re

flect

an

ce

Tra

nsm

itta

nce

Energy (cm-1)Energy (cm-1)

Content Measured by HPLC Content Measured by HPLC

Ca

lcu

late

d

Co

nte

nt

Ca

lcu

late

d

Co

nte

nt

Data Range: 4000 – 10000cm-1 Data Range: 8600 – 10000cm-1

Division of Pharmaceutical AnalysisSt. Louis, Mo. and White Oak, Md.