Mobilní analyzátory a jejich využití ve farmaceutickém průmyslu

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Mobilní analyzátory a jejich využití ve farmaceutickém průmyslu Tomáš Černohorský Univerzita Pardubice Fakulta chemicko-technologická Ústav environmentálního a

1 Mobilní analyzátory a jejich využití ve farmaceutickém průmyslu Tomáš Černohorský Univerzita Pardubice Fakulta chemicko-technologická Ústav environmentálního a chemického inženýrství Centralizovaný rozvojový projekt MŠMT č. C29: Integrovaný systém vzdělávání v oblasti výskytu a eliminace reziduí léčiv v životním prostředí

2 Mobilní analyzátory aktuálně využívané a perspektivní technologie Ramanova spektrometrie, SERS Ramanova spektrometrie FT IR spektrometrie NIR spektrometrie IMS spektrometrie Hmotnostní spektrometrie Spojení separačních technik a hmotnostní spektrometrie Mikrofluidické chipové technologie

3 Mobilní analyzátory obory využití ve farmaceutickém průmyslu Kontrola vstupních surovin (RMID Raw Material ID) Mezioperační kontrola Výstupní kontrola Kontrola padělků léčiv a substandardních produktů Screeninkové metody pro kontrolu znečištění v odpadních vodách

4 Ramanova spektrometrie, FT IR a NIR spektrometrie Raman characterizes materials by the frequencies of their molecular vibrations Mid-infrared (MIR aka FTIR) Near-infrared (NIR)

5 IR Absorption versus Raman Absorption/Reflectance all wavelengths in some wavelengths absorbed/reflected Raman Scattering single wavelength (laser) multiple wavelengths emitted

6 amount of light scattered Molecular Vibrations Raman fingerprint of the molecule Shifted wavelength of light scattered

7 What is Raman?

8 Introduction to FTIR Spectroscopy FTIR is based on measurement of the wavelengths that are absorbed as a result of the interaction with the sample. Absorbed wavelengths = Unique Fingerprint

9 Molecular Excitation Molecules can be excited when they are exposed to energy the more energy, the more excited they become. With a gentle nudge they become vibrationally excited (think wobbling bowl of jello). vibrational enery levels Energy (wavenumbers) 20,000 first electronic excited state 4,000 vibrational enery levels 0 electronic ground state

10 Molecular Excitation vibrational enery levels Energy (wavenumbers) 20,000 first electronic excited state 12,738 4,000 vibrational enery levels 0 IR absorption (e.g., FTIR) electronic ground state

11 Molecular Excitation vibrational enery levels first electronic excited state Rayleigh 12,738 Raman virtual excited state 785nm excitation Energy (wavenumbers) 20,000 4,000 vibrational enery levels 0 IR absorption electronic ground state

12 ABSORPTION v. RAMAN KIC K FTIR La se rp rov i de st he Raman ground state

13 Raman Spectrum Rayleigh scatter Raman scatter Raman shift (cm-1) {change in energy}

14 FTIR, Raman Spectra

15 Dextrose, Monohydrate FTIR NIR excellent selectivity requires contact / prep less selectivity non-contact / no prep * RAMAN typical range excellent selectivity non-contact / no prep wavenumbers (cm-1)

16 -1 [ x 1] 0 Citric Acid C itr ic A c id ( G r o u n d ) N IR.s p c 7 6 Near-Infrared Good A r b itr a r y [ x 1] C it r ic Wavelength (micrometers) A c id. s p c 4.0 (FTIR) 3.5 A b s o rb a n c e Mid-Infrared Better [ x ] C it r ic Wavenumber (cm-1) A c id. s p c Best 4.5 A r b itr a r y Raman Wavenumber (cm-1)

17 Fluorescence Fluorescence Is an optical phenomenon where a molecule is electronically excited by absorbing photons The molecule then relaxes by emitting photons Drives the operation of TV s, fluorescent lights, etc. Can also be problematic in Raman spectroscopy laser

18 Fluorescence Looks like this the broad background is due to fluorescence. It is an additional source of noise, and if present, will slow down the data acquisition (in extreme cases, even prohibiting data acquisition) counts spectrum of animal-derived monoglycerides example moderate fluorescence, but suitable for material ID spectrum of soy protein example of extreme fluorescence Raman shift ( cm-1)

19 Mobilní analyzátory Identifikace vstupních surovin

20 From Spectrum to Identification Scan spectrum Match Library spectrum Identification!

21 Specificity dextrose monohydrate dextrose anhydrous fructose sucrose lactose monohydrate glucosamine HCl trehalose Raman shift ( cm-1)

22 Identity Testing: Is this material what it claims to be?

23 Traditional RMID Workflow 23

24 The handheld Raman Solution for RMID Workflow Typically < 6 months 24

25 Progression of Raman Instruments 25

26 Thin-Pack Spectrometer, Handheld Example Hermetically Sealed Enclosure for CCD CCD Chip and TE Cooler Raman Probe Imaging mirrors Grating Grating-Stabilized Laser Collimating and Focusing Optics Lasing substrate 26 Focusing Optics

27 microphazir Rx 27

28 MATERIAL A MATERIAL C MATERIAL B

29 System must be a slave to the objective Factors influencing the measurement and measurement uncertainty INSTRUMENT measurement MATERIAL ENVIRONMENT uncertainty NECESSITATES SUFFICIENT RESOLVING POWER 2000-dimensional

30 Example of Instrumental Factors

31 MATERIAL A MATERIAL C MATERIAL B

32 Material Identification (which one is it?) unknown pentaethylene glycol tetraethylene glycol triethylene glycol Raman shift ( cm-1) 1600

33 Material Identification (which one is it?) pentaethylene glycol tetraethylene glycol triethylene glycol Raman shift ( cm-1) 1600

34 Material Identification (which one is it?) pentaethylene glycol tetraethylene glycol triethylene glycol Raman shift ( cm-1) 1600

35 Material Identification (which one is it?) pentaethylene glycol tetraethylene glycol triethylene glycol Raman shift ( cm-1) 1600

36 Reality tends to look like this MATERIAL B MATERIAL A ENORMOUS class separation between materials MATERIAL C

37 TruScan System Logic reference (library) measurement determine if aspects of measurement statistically contradict reference model NO PASS (no Raman evidence to believe otherwise) 37 YES Suspect (Raman evidence of discrepancy)

38 Decisive Results p-value = 0.57 ephedrine HCl (measured) ephedrine HCl (reference) p-value = 3.1x10-12 ephedrine HCl (measured) pseudoephedrine HCl (reference)

39 Authentication of phenol Reactive mass-classifier (Pr(D H)) 39 HQI phenol benzaldehyde benzoic acid benzyl alcohol toluene

40 Mobilní analyzátory mezioperační kontrola Raman FT IR NIR IMS viz. dále

41 Mobilní analyzátory detekce padělků léčiv a substandardních produktů Primární technika Ramanova spektrometrie Doplňková technika NIR Doplňková technika digitální mikroskopie a analýza obrazu

42 Is this what it is SUPPOSED to be? 42

43 Counterfeit Drug Prevalence Estimates Russia 10% EU 1% US 1% Lebanon 35% Mexico 10% Source: 2006 WHO Report China 8% Columbia 5% India 20% Nigeria 16% Kenya 30% Indonesia 25%

44 What is a counterfeit drug? No consistent, universally agreed-upon definition exists, making regulation and enforcement difficult. WHO s definition: A counterfeit drug is a drug that has been deliberately and fraudulently mislabeled with respect to identity and/or source. Counterfeiting can apply to both branded and generic products and may include products with the correct ingredients or with the wrong ingredients, without active ingredients, with insufficient active ingredients or with fake packaging.

45 Counterfeit vs. Substandard drugs Low quality product (degraded, insufficient ingredients, incorrect ratio of ingredients, wrong ingredients, lack of registration or documentation) SUBSTANDARD DRUGS COUNTERFEI T DRUGS Willfully mislabeled as to identity or source

A Complex Problem Substandard medicines: Products whose composition and ingredients do not meet the correct scientific specifications, and are

46 A Complex Problem Substandard medicines: Products whose composition and ingredients do not meet the correct scientific specifications, and are potentially dangerous Counterfeit (falsified) medicines: Products deliberately and fraudulently mislabeled with respect to identity and/or source.

47 Which is which? Real and Fake Tamiflu..Can you tell the difference?

48 Authentic Viagra tablet, 100mg dose Titanium oxide(anatase) Viagra 100mg Sildenafil Lactose Raman shift ( cm-1)

49 Counterfeit Viagra breakdown Unknown Calcium sulfate hemihydrate Titanium oxide, anatase Sildenafil Raman shift ( cm-1)

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