The RamanRxn Systems™ family of instruments is ideal for analyzing, monitoring, and controlling chemical processes. Raman spectroscopy provides the chemical specificity of a mid-IR analyzer with the ease of sampling of a near-IR analyzer. Instruments in the RamanRxn Systems family are the preferred analytical tools for in situ crystalline polymorph and aqueous-based reaction analysis and monitoring.

The RamanRxn1™ analyzer incorporates the latest TE-cooled CCD detector technology for maximum sensitivity, a high-powered Invictus™ NIR laser to minimize fluorescence, and HoloPlex™ grating technology to provide fast, simultaneous full spectral collection of Raman data. Fiber optic sampling and probe technologies enable the RamanRxn1 analyzer to analyze, in real time and in situ, sample volumes ranging from 5 mL to 5000 gallons. Advanced calibration protocols permit chemical models developed in the laboratory to be easily transferred to pilot or production reactors.

Within the RamanRxn Systems family, configurations are available for control room operation or operation within classified areas.
 

Solutions & Applications

• Crystallization studies
• Hydrogenations
• Catalysis investigations
• Polymorphic form ID
• Emulsion polymerizations

System Benefits

• Specificity of mid-IR, but with the ease of sampling of near-IR
• No sample preparation required
• Accurate transfer of calibration models from lab-to-pilot-to-plant systems
• Simple to learn, easy to use

Sampling Technology

• Fiber-optic probehead for in situ, real-time analysis
• Optimized for low-wavenumber performance
• Hastelloy® immersion optics: temps to 280 ºC, pressures to 3000 psi
• Non-contact optics for focusing beam through site windows

Software Features

• Real-time analysis
• Visualize chemical trends
• Create quantitative analysis models

The hydrolysis of acetic anhydride to acetic acid was monitored inside a glass calorimetric reaction vessel using a standard immersion probe. Although this reaction occurs fairly quickly, the RamanRxn1 analyzer can easily follow the conversion of acetic anhydride (675 cm^-1) to acetic acid (893 cm^-1).

Introduction

• The pharmaceutical industry frequently encounters multiple polymorphs for the same chemical entity.
   
• These polymorphs may have different properties, e.g., solubility, dissolution rate, stability, or bioavailability.
   
• The RamanRxn1 analyzer is able to discriminate between polymorphs because different crystal forms provide intensity and frequency changes in the Raman spectrum.
   
• The Raman technique can be applied without sample preparation and allows for non-destructive and in situ measurements.
   
• Aqueous and non-aqueous reaction systems can be monitored with the RamanRxn1 analyzer.
   
• The RamanRxn1 analyzer permits robust chemical modeling that facilitates calibration transfer.
   
• Fiber-optic sampling locates the analyzer outside classified environments, simplifying application transfer to pilot and production plants.

Solvent-Mediated Polymorphic Transformation of Progesterone

Progesterone

Progesterone is both an important active agent and chemical intermediate in the pharmaceutical industry.   There are five identified progesterone polymorphs.   Off-line techniques have been used to accurately determine end product polymorphs.   Unfortunately, off-line analysis cannot provide dynamic information about phase transformation processes.   In this study, forms I and II are characterized by Raman spectroscopy.   In situ Raman is then used to actively monitor the solvent-mediated polymorphic transformation of progesterone from form II to form I.

Raman Spectra of Progesterone Crystal Forms I and II

Numerous spectral differences are apparent between the two polymorphs.   For this study the C=O stretching vibration was used to quantitate form I and form II polymorphs. Form I @ 1662 cm-1. Form II @ 1667 cm-1.

Progesterone Solvent-Mediated Polymorphic Transformation at 45° C

Slurry: 2 g progesterone (25 mL organic sol.) was added to 500 mL H2O .   Replicate measurements carried out from 5 to 45 °C.

Conclusions

• The RamanRxn1 analyzer can distinguish form I and form II progesterone crystals.
   
• The RamanRxn1 analyzer was shown to accurately follow the polymorphic transformation (form II to form I) in situ.
   
• Transformation rates were found to increase with increasing temperature.
   
• This indicates that form I and form II progesterone are monotrophs.
   
• These conclusions were supported by XRD and DSC techniques where appropriate.
   
• The in situ monitoring of this system permits the rate of polymorphic transformation to be predicted over a wide range of process temperatures.
   
• The use of fiber-optic sampling will simplify the transfer of in situ Raman monitoring to pilot and production plants.