The Role Of Solid State NMR Spectroscopy Biology Essay

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Introduction: Solid-state NMR is a powerful, but subtle, technique for the characterisation of solid materials.  It is strongly complementary to diffraction-based techniques in that it probes local chemical environments and so can be applied successfully to crystalline or homogeneous.  However, the equipment required considerable expertise to use the technique effectively. solid state NMR can be used for instance, to measure internuclear distances, quantitatively, which enable to determine the conformation of molecule, length of hydrogen bond and bond angle without a crystalline lattice and useful in inhomogeneous or amorphous systems.[1]

Solid state NMR spectroscopy is extremely useful technique for the analysis of pharmaceutical compound and provides a wealth of information about the physical and chemical state of pharmaceutical compound. Solid sate NMR spectroscopy is now used extensively in pharmaceutical analysis, from polymorph identification all the final dosage form characterisation by identifying and quantifying polymorphs and mixtures of polymorphs and amorphous. Drug and expedients can be analysed without sample preparation by making it non destructive technique.[2] Solid state NMR can apply to study phase transition, drug-Excipients interaction, drug stability and reaction in solid phase.[3]

Solid state NMR spectra of pharmaceutical solids are acquired using cross polarisation (CP) with magic-angle spinning (CPMAS), mostly with 13C detection. CPMAS is a double resonance technique with cross polarisation facilitates magnetization transfer from abundant spins to dilute spins.1H to 13C cross polarisation results in a fourfold increase in sensitivity relative single pulse c experiments, and the time between each acquisition become much shorter because 1H spin lattice relaxation time determines repeat rate. Magic Angle Spinning (MAS) serves to reduce or eliminate the homogeneous broadening effects of chemical shift anisotropy such that only the isotropic chemical shift is observed. Solid state NMR spectra can provide to characterise pharmaceutical compounds and abilities are

Ability to identify different forms of drugs (API) and Excipients.

Difference in relaxation times between crystalline drugs and amorphous Excipients and,

Ability to study complex amorphous systems consisting of drug and Excipients. [4]

Polymorphic and amorphous compound identification: A solid state NMR spectrum is well suitable for study of polymorphism because small changes in conformation and local electron structure cause observable difference in chemical shift. Mostly Xry Diffraction (XRD) technique used for identification of polymorphic forms. If polymorphic changes occurs during the formulation process than detection limit of XRD may not be great. Solid state NMR is capable of detecting different polymorphs. The small chemical shift differences of polymorphs are not always observable due to the larger line width. Conformation differences can result in variations in local electron density and NMR can be an ideal probe for this type of behaviour, via the chemical shielding tensor. [5-6] Solid state NMR is able to resolve different polymorphs because of stability and changing hydrated form. For all of these reasons solid state NMR is widely used for characterisation pharmaceutical compound.

Unfortunately, due to overlapping spectral feature in some organic compound, analysis of chemical shift in 1D MAS is nearly impossible. In this case 2D solid state NMR techniques have been suggested for separation of isotropic and anisotropic parts of spectra. [7]

For amorphous materials, the crystallographically technique detect conformational changes and hydrogen bonding. More advanced, two dimensional techniques also use to measure distance. In amorphous material solid state NMR use to examine degree of disorder because various techniques can vary in sample. Crystalline form is less stable than other forms because of their molecular mobility. In the NMR spectra of amorphous material, peaks are roughly ten times broad on position relative to crystalline peaks and that provide the presence of amorphous material in sample, because detection limit for amorphous material is 10%-20% based on peak location. [8]

Analysis of solid dosage forms: Solid dosage forms contain active pharmaceutical ingredients (API) and Excipients. It is important to characterise properties of bulk API and Excipients because it has dramatically effect on dissolution rate, bioavailability and stability so API should be pure for good final product. [9]

Advantage of solid state NMR to other analytical techniques: It is non invasive and non destructive method and usually it does not require any sample preparation. It can apply to the active substance as well as formulation at each production step to monitor changes in physical form. Technique is highly sensitive to change in local environment so it is possible to identify polymorphs and amorphous material. Quantification of different components of a mixture can be achieved if the technique is performed properly; the intensity of the peaks is directly proportional to the number of magnetically equivalent nuclei.

Disadvantage: The main disadvantage is related to high cost of spectrometer and the technique is non-routine and require highly trained operator. Selective isotopic enrichment of certain sites in the molecule shortens the acquisition time by increasing the sensitivity so expense increase dramatically. [10]

Solid state NMR gives information on bulk drugs and formulation, quantitation of forms, conformation and arrangement of molecules and study of molecular dynamics.

Study of solid dosage analysis are based on differences in C isotropic chemical shift and line widths among solid dosage forms so it mainly consist analysis of C MAS. This approach can extended to the investigation of solid dispersions which is provided from the signals of API and Excipients but Excipients are usually present in large amount than API. Excipients are mostly carbohydrates and API usually contains aliphatic, aromatic or carbonylic carbons and which correspond typical spectra regions. [11]

Prednisoline structure

Form I

Form II

Solution

Carbon Atom

209.5

211.8

211.5

C(20)

188.1

187.9

185.1

C(3)

175.1

171

170.5

C(5)

159.8

157.3

156.8

C1()

125.9

130.2

127.2

C(2)

121.8

123.8

121.7

C(4)

91.4

90.2

88.5

C(17)

69.9

70.4

68.6

C(11)

67.1

67.7

66.1

C(21)

55.4

54.8

55.5

C(9)

52.2

52.8

51.2

C(14)

47.5

47.1

46.7

C(13)

45.3

45.1

43.9

C(10)

42.1

43.1

39

C(12)

35.3

34.7

34.1

C(8)

34.3

33.5

33

C(16)

33.5

32.7

32.7

C(15)

31.8

31.5

31.6

C(6)

24.6

25.4

31.2

C(7)

23.9

23.7

21

C(18)

17.3

18.1

17

C(19)

Table .1 shows chemical shift of two forms of prednisolone along with peaks assignments

From table, the major chemical shift differences between two forms are for C (2) by 4.3 ppm and C (5) by 4.1 ppm. (This table, structure and spectra of prednisolone taken from "solid state NMR spectra of Pharmaceutical Dosage Forms by Patricia J. Saindon, Nona S. Cauchon, Paul A. Sutton, C. J . Chang, Garnet E. Peck, and Stephen R. Byrn)

Figure.1 Solid state CP/MAS spectra of Prednisolone 5mg tablets from two manufactures (form I and form II) aromatic signals resonated in Excipients free spectra region.

Figure shows solid state 13CNMR spectra of Prednisolone and it clearly shows that form I contain form II. This can clearly see by comparing the splitting of peaks between 120 to 140 ppm in figure 2.

The spectra of Prednisolone shows two closer peaks and it shows that solid state NMR can be use to determine the polymorph present in dosage form even drug is in small amount. [12]

Conclusion: Solid state NMR is an excellent technique for analysis of pharmaceutical compound. It has some disadvantages but it has many advantages over other analytical techniques. Though it is a last chance technique because of cost and requires expertise to handle it.

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