14 N Nuclear Quadrupole Resonance Study of Polymorphism in Famotidine

RESEARCH ARTICLE – Drug Discovery Development Interface

14N Nuclear Quadrupole Resonance Study of Polymorphism inFamotidine

JANKO LUZNIK,1 JANEZ PIRNAT,1 VOJKO JAZBINSEK,1 ZORAN LAVRIC,2 VESELKO ZAGAR,3 STANE SRCIC,2

JANEZ SELIGER,3 ZVONKO TRONTELJ1

1Institute of Mathematics, Physics and Mechanics, Ljubljana, Slovenia2Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia3Institute J. Stefan, Ljubljana, Slovenia

Received 19 December 2013; revised 14 February 2014; accepted 28 February 2014

Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.23956

ABSTRACT: 14N nuclear quadrupole resonance (NQR) in two known polymorphs of famotidine was measured. At room temperature,seven quadrupolar sets of transition frequencies (�+, �−, and �0) corresponding to seven different nitrogen sites in the crystal structureof each of the two polymorphs were found. This confirms the expected ability of NQR to distinguish polymorph B from its analog A.NQR can also measure their ratio in a solid mixture and in the final dosage form, that is, a tablet. The NQR frequencies, line shapes,and tentative assignation to all seven molecular 14N atoms were obtained. Unravelment of these two entangled NQR spectra presents avaluable contribution to the NQR database and enables studies of some possible correlations therein. Moreover, nondestructive 14N NQRstudies of commercial famotidine tablets can reveal some details of the drug fabrication process connected with compression. C© 2014Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm SciKeywords: crystal structure; crystal polymorphism; spectroscopy; analysis; polymorphism; tableting; solid-state NMR; database

INTRODUCTION

The pharmaceutically active substance famotidine is used intherapy of stomach and duodenal ulcers, in reducing ulcer pain,in treatment of gastroesophageal reflux disease, and so on.

Nuclear quadrupole resonance (NQR) is a nondestructive,contactless radiofrequency (RF) spectroscopic method. Solidsamples in their final form (powders, granulates, tablets, pel-lets, etc.) can be examined without any modification, even intheir original packaging.1 14N nuclei have spin I = 1 and thusa nonzero electric quadrupole moment. Nitrogen appears in alarge number of organic and inorganic compounds, so 14N NQRcan be very effective in studying their structure, polymorphism,and structural dynamics. As such, the method has potential ap-plication in analysis in the areas of pharmaceutical research,quality control of manufacturing processes, and detection ofcounterfeit drugs.

Polymorphism in drug production is important as the variouspolymorphs can have different mechanical, thermal, physical,and chemical properties,2 which in turn can have a great im-pact on the bioavailability, stability, and tableting processes ofpharmaceutical materials.

Nuclear quadrupole resonance is based on the electric inter-action between nuclei with nonzero electric quadrupole momentand the internal electric field gradient created by the surround-ing electrons whose distribution is determined by the crystalstructure of the solid material.

Abbreviations used: EFG, electric field gradient; MPSE, multipulse spinecho; NQDR, nuclear quadrupole double resonance; QCC, quadrupole couplingconstant; QFS, quadrupolar frequency set (<+, <−, and <0).

Correspondence to: Janez Pirnat (Telephone: +386-1-4766579; Fax: +386-1-2517281; E-mail: [email protected])

Deceased.

Journal of Pharmaceutical SciencesC© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association

The nitrogen 14N NQR frequencies are given by theexpression3,4

<+ = e2qQ4h

(3 + 0) , <− = e2qQ4h

(3 − 0) , and <0 = e2qQ2h

0. (1)

Here, e2qQ/h = QCC is the quadrupole coupling constant whereeQ is the nuclear electric quadrupole moment, eq = qzz is themaximal principal value of the electric field gradient (EFG)tensor, e is the unit charge, h the Planck constant, and 0 =0= (qxx − qyy)/q is the EFG asymmetry parameter.

In the case of famotidine5–7 (Fig. 1), there are seven nitrogenatoms per molecule, that is, seven nonequivalent positions inits monoclinic crystal structure. Seven “quadrupolar frequencysets” (QFS) of the lines <+, <−, and <0 appear for each polymor-phic form.

Famotidine is an excellent histamine H2 receptorantagonist.8 It crystallizes in two different polymorphic forms,stable at room temperature. Both polymorphs belong to themonoclinic crystal system with four molecules per unit cell,however, with different unit cell dimensions. For the thermo-dynamically more stable polymorph A, the dimensions are6

a = 11.912 A, b = 7.188 A, c = 16.624 A, and $ = 100.045◦;for the polymorph B, which is most often favored in crystal-lization kinetics, a = 16.980 A, b = 5.285 A, c = 17.639 A, and$ = 116.416◦. Since polymorphism can influence the aqueoussolubility of a pharmacologically active drug, characterizationof its crystal form is of great importance.

MATERIALS

Famotidine was obtained from the pharmaceutical companyKrka (Novo mesto, Slovenia). The raw material of famotidine

Luznik et al., JOURNAL OF PHARMACEUTICAL SCIENCES 1

2 RESEARCH ARTICLE – Drug Discovery Development Interface

Figure 1. Famotidine molecule (2D projection): enumeration andfolding of the atoms in polymorph A (panel a) and the same for poly-morph B (panel b).5,6.

was of pharmaceutical grade and the analytical methods to bedescribed in the next sections [differential scanning calorimetry(DSC), FTIR, NQR] proved it to be of pure polymorphic form B.Therefore, this form was used for our measurements withoutfurther treatment.

Famotidine in form A was prepared by recrystalizationfrom an aqueous solution of the raw material.7,9 Raw famo-tidine (polymorph B) was dispersed in water at a concen-tration of 10 mg/mL. Temperature of the mixture was thenincreased to 80◦C and kept there for a few minutes. The so-lution was filtered and left to cool slowly (about −50◦/h) toroom temperature. The suspension of precipitated polycrystalswas filtered and the product—polymorph A—was dried at roomtemperature. Finally, the sample was analyzed as describedbellow.

So, both investigated materials were easily attained in purepolymorphic forms.

Preparation of Compacts

Famotidine (form B) powder was compressed on a Killian SP300(IMA, Cologne, Germany) eccentric single punch tablet pressusing round flat-faced punches (diameter 12.0 mm). The tabletpress was operated in the manual mode. Compacts weighingaround 600 mg were prepared at three compression forces (5,10, and 30 kN).

ANALYTICAL METHODS

Differential Scanning Calorimetry

A DSC 1 Calorimeter from MettlerToledo was used to analyzesamples in the temperature interval from 25◦C to 180◦C at aheating rate of 5 K/min while purging the sample compartmentwith a stream of nitrogen gas at 50 mL/min. Samples wereplaced in closed 40 :L Al pans that were lid-pierced just priorto the measurement.

Attenuated Total Reflectance–FTIR

A Nicolet Nexus FTIR spectrometer from the Nicolet Instru-ment Company (Madison, WI) equipped with a diamond ATRDuraSamplIR attachment from Danbury Technologies wasused for IR analysis of the samples.

14N Nuclear Quadrupole Resonance

We used a standard pulsed NQR spectrometer consisting of (1)a tank circuit with the sample and a preamplifier, (2) a pro-grammable rf pulse unit (Spin Core Technologies, Gainesville,FL), (3) an rf power amplifier (Tomco Technologies, BT500 Al-phaS), and (4) a homebuilt receiver. The spectrometer was op-erated from a PC, which was also used for data analysis.

The pulse sequence known as “MultiPulse Spin-Echo”(MPSE)—"0 − (t–2"90–t–)n—was applied.10,11 Here, n is thenumber of repetitions of the basic RF pulse refocusing sequence(t–2"90–t–) in one pulse train, 2"90 indicates that each refocus-ing pulse experiences a 90◦ phase shift relative to the initial"0 pulse, and "0 is the RF pulse width giving the optimal de-tected signal. The sequence of successive pulse trains includingNQR echoes were repeated and accumulated at suitable inter-vals allowing for quadrupole spin–lattice relaxation. Finally,FFT analysis of the averaged quadrupole echo was performedto obtain the spectral lines.

RESULTS AND DISCUSSION

The commercially available form of famotidine is usually purepolymorph B, which was confirmed analytically in our case too.Although it is thermodynamically unstable, its transformationto the thermodynamically more stable form A is practicallynonspontaneous.

Analysis of the form prepared in the laboratory confirmedthat it was pure polymorph A. Neither DSC nor FTIR nor 14NNQR measurements indicated the presence of residual poly-morph B. DSC melting of the laboratory prepared form A oc-curred at 173◦C (∼10◦ higher than form B). No characteristicFTIR peaks of polymorph B were observed in the FTIR spectra:in particular the locally clearly resolved peak at 3505 cm−1 thatwas used previously to determine the content of polymorph Bin the mixture5,7 was absent.

Both polymorphs were found to have a relatively longquadrupolar spin–lattice relaxation time T1 of about 2 s atroom temperature and also long effective transverse relaxationtime T2. The latter enables the use of the MPSE technique with20 or more echoes in a single sequence,10,11 thus multiplies thenumber of averages and improves the final signal-to-noise ratio.

Approximate frequencies of some of the resonance lines infamotidine A and B were found by the double resonance tech-nique NQDR,12–14 but because of the unfavorable experimen-tal conditions, the NQDR signals were rather weak. Thus, to

Luznik et al., JOURNAL OF PHARMACEUTICAL SCIENCES DOI 10.1002/jps.23956

RESEARCH ARTICLE – Drug Discovery Development Interface 3

Table 1. 14N NQR Transition Frequencies at Room Temperature forPolymorphic Forms A and B of Famotidine, Belonging to All SevenDifferent Nitrogen Positions in Each of the Two Crystal Unit Cells

<+ (kHz) <− (kHz) <0 (kHz) QCC (kHz) 0

Form Aa

Na 3455 2443 1012 3932 0.51Nb 2862 2065 797 3285 0.49Nc 2819 2080 739 3266 0.45Nd 2738 2274 464 3341 0.28Ne 2735 2030 705 3177 0.44Nf 2603 1971 632 3049 0.41Ng 1979 1457 522 2291 0.46Form Ba

Nh 3462 2472 990 3956 0.50Ni 2887 2364 523 3501 0.30Nj 2848 2234 614 3388 0.36Nk 2787 2043 744 3220 0.46Nl 2649 2133 516 3188 0.32Nm 2587 1765 822 2901 0.57Nn 1982 1339 643 2214 0.58

aArbitrary enumeration Na,b,c, . . . in order of descending <+. Successive rows(QFS-s) may correspond to different N atoms in form A and form B: Nb →?Ni, Nc

→?Nj, Nd →?Nk, and so on.

unravel all the nitrogen NQR lines and their <+/<−/<0 connec-tions using pure NQR, careful frequency scans and numer-ous trials of the most probable combinations into tentativequadrupolar sets were necessary. The latter process can be te-dious when some lines are still missing. Measurement of theNQR lineshapes in a low magnetic field15 was also performedto discriminate between the <+/<− character of the newly foundlines, and to choose the probable region for further search forthe missing lines.

The measured 14N NQR transition frequencies at room tem-perature and the calculated EFG parameters are collected inTable 1.

The correspondence of the successive QFS-s, that is, the rowsin the upper half of Table 1, to nitrogen atoms in the molecule Ais in general different from the correspondence of QFS-s in thelower half of Table 1 to nitrogen atoms in the folded moleculeB (Nb → ?Ni, Nc → ?Nj, etc.). However, the uppermost rows ofboth Table 1 halves, that is, (1) Na of the polymorph A and (2)Nh of the polymorph B are mutually similar and distinguishedfrom all the other rows; similar statement holds for the QFS-s(3) Ng and (4) Nn in the bottom rows for polymorphs A andB. It seems that at least these two pairs of tensors and thecorresponding QFS-s belong to the two equipositional nitrogensin polymorph A and polymorph B. These two QFS-s seem to bemore “firmly fixed” in both molecular forms A and B (insensitiveto conformational change of the molecule; see Fig. 1).

A tentative assignation was performed considering two cri-teria:

1. Relative mutual similarity of the two chosen QFS-s whenpassing from polymorph A to B and their resemblance toQFS-s of known NQR spectra of other compounds withsimilar local molecular structure.17,19,22

2. The correlation between the two pairs <+/<− of the twotentatively equivalent nitrogen sites of the polymorphsA and B, should agree with the same empirically af-firmed <+/<− correlation, characteristic for many other

Figure 2. Empirical correlation between 14N quadrupole frequencies<+ versus <− in the environment of an amino group bound to a guanidineion.22

molecules, containing the relevant structurally equiva-lent nitrogen surroundings16–22 (cf. Fig. 2).

Lines Na, Nh → N18: The two highest QCC-s belong to the linesets Na of polymorph A and Nh of polymorph B. Both tensorsresemble those of the sulfonamide group in sulfanilamide andsimilar compounds.16–18 Therefore, the QFS-s Na (polymorph A)and Nh (polymorph B)—both lying near the frequencies <+ ∼3.5 MHz, <− ∼ 2.5 MHz, and <0 ∼ 1 MHz—are ascribed to theS17—N18H2 nitrogen, located in the “sulfa” tail of the famotidinemolecule (criterion (1)).

Lines Ng, Nn → N3: The spectra of the five-membered imida-zole ring compounds were studied in Refs. 19 and 20. There,an empirical correlation for the imino nitrogen frequencies wasfound:

<− = 1.9137<+ − 2505 kHz. (2)

The imidazole ring is present in famotidine too and the aboverelation is sufficiently well met (better than 87%) in the QFS-sNg (polym.A) and Nn (polym.B), belonging to the lowest twoQCC-s (Table 1). Thus, those two spectra are assigned to theimidazole nitrogen N3 in famotidine (for both polymorphs A, Bboth criteria (1) and (2) approximately fulfilled).

Lines Ne, Ni → N15: Another NH2 nitrogen attached to C14 inthe famotidine chain constitutes the C14—N15H2 group next tothe “sulfa” tail. Compounds with such a group were studied inRef. 21. The empirical spectral correlation for a nitrogen atomof this kind was found to be:

<− = 1.7027<+ − 2581 kHz. (3)

The above relation is best obeyed in the following famotidineQFS-s from Table 1: Ne of polymorph A and Ni of polymorphB (better than 98%). Thus, those lines are assigned to nitrogenN15 (criterion (2)).

Lines Nb, Nc, Nk, Nm → N8/N9: The remaining two “twin”NH2 groups are both bound to the same carbon C7 in the “guani-dine” tail of famotidine. These two nitrogens can be compared

DOI 10.1002/jps.23956 Luznik et al., JOURNAL OF PHARMACEUTICAL SCIENCES


Table 2. Typical Example: Agreement of the MeasuredQuadrupole-Frequency-Set Pairs of Nb, Nc, and Nk, Nm with theCorrelation (4) (better than 91%)

<+ /kHz <- calc. /kHz <- meas. /kHz

Form A: Nb,Nc 2862 2056 20652819 1987 2080

Form B: Nk,Nm 2787 1986 20432587 1618 1765

with the amino groups of the guanidine ion whose NQR spectrawere studied in Ref. 22. In Figure 2, we plotted the empiricalcorrelation diagram of the relevant NQR frequencies <+ and <−.The best-fitted linear relation for the experimental points is

<− = 1.59<+ − 2495 kHz. (4)

The two pairs of QFS-s in each famotidine polymorph, that is,Nb, Nc and Nk, Nm, obey this correlation reasonably well (cf.Tables 1 and 2). Thus, the two amino groups N8H2 and N9H2

from the “guanidine” tail are assigned to the spectra Nb andNc of polymorph A and to Nk and Nm of polymorph B (criterion(2)).

Lines Nf, Nd, Nl, Nj → N6/N16: In the above assignation pro-cedure, two nitrogens remain undetermined: N6 on the “guani-dine” side of the famotidine chain (group C7==N6—C2) and N16

on the “sulfa” side (group C14==N16—S17). With our presentunderstanding these two nitrogens could only be alternativelyconnected with any of the remaining QFS-s Nf or Nd of poly-morph A and with Nl or Nj of polymorph B.

To summarize, three assignations are rather firm: N3, N15,and N18 to the sets Ng, Ne, Na in polymorph A and to the setsNn, Ni, Nh in polymorph B (enumeration as in Refs. 5 and 6.Only a pairwise assignation is possible for the two leftmost“twin” NH2 nitrogens N8 and N9, which play equivalent rolesin the isolated molecule. Their QCC-s apparently move togetherdownward when transforming polymorph A (N8, N9 → Nb/c) topolymorph B (N8, N9 → Nk/m). Further, it is also difficult todifferentiate between the nitrogens N6 (group C==N—C) andN16 (in C==N—S). But only two possible NQR line sets can bealternatively ascribed to either of these two nitrogen sites foreach polymorph: Nf/d in polymorph A and: Nl/j in polymorph B.Figures 3 and 4 represent tentative assignations of 14N NQRspectra of polymorphs A and B of famotidine. Figure 4 shows

Figure 3. Summarized tentative assignation of the nitrogen atomsNi from Figure 1 (1st text line) to the NQR line sets from Table 1;2nd line—our assignation in polymorph A; 3rd line—our assignation inpolymorph B. Bold font is used to indicate firmer (unique) assignations.

Figure 4. Graphical representation of the seven 14N QCC-s in thetwo polymorphs A and B of famotidine. For the sake of clarity, inthe case of two possible QCC-s, only one point instead of two, thatis, the average QCC, is plotted. These four “questionable” points, indi-cated by question marks, correspond to those two N pairs, which arehard to distinguish by their spectra: N8/N9 and N6/N16.

that the distribution of the principal values of seven nitrogenquadrupole tensors along the famotidine chain remains quali-tatively similar in both polymorphs A and B. Different foldingbrings about only minor frequency shifts, which are howevereasily measured and resolved.

To characterize the polymorphic composition of an unknownfamotidine sample there is no need to scan the whole frequencyrange. One may select a very narrow frequency interval cover-ing only two closely lying 14N NQR transition frequencies—onefor each polymorph. The intensities of different 14N NQR tran-sition lines and also their relaxation properties are not equal.The best choice is to select a pair with the maximal intensity,which allows the greatest number of echoes in a single multi-pulse sequence. According to our experience, such pairs of linesare: 2603 kHz of polymorph A and 2587 kHz of polymorph B,2862 kHz of polymorph A and 2887 kHz of polymorph B or 3455kHz of form A and 3462 kHz of form B. Each of the three pairsof 14N NQR transition lines can be observed simultaneously inthe same spectral region for both polymorphic forms (Fig. 5).From the 14N NQR spectra, it is possible to quantify the

Figure 5. Typical characteristic part of the 14N NQR spectrum for amixed sample of forms A and B of famotidine (approximately 75% formA and 25% form B).


RESEARCH ARTICLE – Drug Discovery Development Interface 5

Figure 6. Dependence of 14N NQR relative linewidth on compactingpressure of tablet fabrication for the 2587 kHz line (relative linewidthin unpressed powder = 1). The relative linewidth of the same 14N NQRline in “Ulfamid” is indicated by the dotted straight line.

polymorphic form and its purity. Additionally, for samples ofheterogeneous mixtures of polymorphs and excipients, it is pos-sible to determine the concentration of different polymorphs.This is of special interest in studying transitions from one poly-morphic form to the other.23

Commercially available tablets of “Ulfamid” (Krka Pharma-ceutical Company) containing famotidine were also tested. Our14N NQR measurements show that the sample contains only thepure form B of famotidine. However, the corresponding NQRlines are broader than those in the powder sample. In our expe-rience, the compacting pressure used during the manufactureof tablets can influence the 14N NQR linewidth.24 To confirmthis assumption, we prepared our own tablets from a powdersample (B) using different compacting pressures. The depen-dence of the 14N NQR linewidth on the compacting pressurefor famotidine tablet preparation was successfully examined(Fig. 6).

CONCLUSIONS

The complete 14N NQR spectra in two polymorphs of famotidine(seven pairs <+/<− for polymorph A and 7 pairs for polymorphB) at room temperature were measured, verified by measuring<0 and analyzed.

A possible application of the NQR technique for nondestruc-tive quantitative determination of polymorph composition wasdemonstrated.

A tentative assignment of all seven measured quadrupolarsets (<+,<−,<0) was proposed for all nitrogen atoms in the famo-tidine molecule, polymorphic form A, and polymorphic form B.

Some of the NQR lines were also studied in commercialtablets containing famotidine (Ulfamid, Krka). The influenceof compacting pressure on 14N NQR line broadening duringthe manufacture of tablets of famotidine polymorph B was con-firmed. Such a dependence on compaction process could be usedto identify the manufacturer.

ACKNOWLEDGMENTS

The study was partly funded by the EC FP-7 project CON-PHIRMER (GA Nr. 261670) and by the Slovenian ResearchProgram PR-0348. Donation of the famotidine B sample by theKRKA pharmaceutical company (Krka, Tovarna Zdravil, d.d.)is highly appreciated.

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14 N Nuclear Quadrupole Resonance Study of Polymorphism in Famotidine