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Division of Pharmaceutical Analysis. Lucinda F. Buhse, Ph.D., Director. Research in support of the Critical Path Dimensions Ensuring Safety Demonstrating Medical Utility Industrialization Process. Division of Pharmaceutical Analysis Critical Path Initiatives.

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Division of Pharmaceutical Analysis

Lucinda F. Buhse, Ph.D., Director

Research in support of the Critical Path Dimensions

Ensuring Safety

Demonstrating Medical Utility

Industrialization Process

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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)

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Characterization of Novel Dosage Forms/ Complex Drug Substances


  • 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

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Monitoring Liposomal Drug Products (LDPs) SubstancesUnder Manufacturing Stress Conditions

LDPs (PEGylated Doxil ®, Conventional DaunoXome®)

Stress Conditions



Acid and Base




Analytical methods for Monitoring quality

Drug Substance (HPLC-UV)

Encapsulation Efficiency (fluorescence)

Lipid Composition (HPLC-ELS)

Particle Size

Zeta Potential

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Several sizes of patches, types of drug delivery, application periods, and shapes.

Transdermal Drug Delivery Systems: Adhesive Strength

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

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Measurement and ID of Micro and Nanoparticles application periods, and shapes.


  • 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

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Establishment of Appropriate Surrogate Measurement Techniques


  • 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

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Dissolution: Less variability is needed Techniques

  • 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

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Drug Authenticity and Anti-counterfeiting Techniques



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

    Regulatory Accomplishments:

  • Quality of foreign Active Pharmaceutical Ingredients program

  • Foreign Internet Sample Studies

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IRMS- Isotope Ratio Mass Spectrometry Techniques

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.

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Process Analytical Technologies for Manufacturing Techniques


  • Assessment of technologies for PAT (Terahertz, NIR)

  • Effect of coating composition and thickness on PAT measurements

  • Effect of excipient and excipient/drug interaction

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Terahertz Absorption Spectra Techniques

Partial Least Squares Fit

THz Predicted Content (mg)


Content (mg) by NIR PLS Calibration from HPLC

Energy (5 - 45cm-1)

  • Non-Destructive and Penetrating

  • Imaging of Biological Tissue

  • On-Line or At-Line Quality Control including whole tablet imaging

Terahertz Spectrometry

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

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Computational Chemistry Techniques(Chemometrics)


  • Understanding chemometric software packages

  • Understanding limitations and benefits of multivariate techniques

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Uncoated Acetaminophen tablets in 9 dosage levels 65 – 135mg.

Critical Path - Chemometrics

Tablet Reflectance – full range

Tablet Transmittance – limited spectral range

Data Range: 4000 – 10000cm-1

Data Range: 8600 – 10000cm-1



Near Infrared Reflectance and Transmittance of formulated tablets

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

Energy (cm-1)

Energy (cm-1)

PLS – Mean Centered, 2nd Derivative, 3 Factors

PLS – Mean Centered, Direct Spectra, 3 Factors

Calculated Content

Calculated Content

Content Measured by HPLC

Content Measured by HPLC

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Division of Pharmaceutical Analysis 135mg.St. Louis, Mo. and White Oak, Md.