IEEE EUROCON 2017

6 8 July 2017 Ohrid, Republic of Macedonia

Modeling the Solid-state Vibrational Spectroscopic

Properties of Morphine-based Formulations With
Hybrid Meta Density Functional Theory
Bojana Koteska1, Anastas Mishev1, Marija Glavas Dodov2, Maja Simonoska
Crcarevska2, Jasmina Tonic Ribarska2, Vesna Petrovska Jovanovska3, Monika
Stojanovska3, Ljupco Pejov4
1Faculty of Computer Science and Engineering, 2Faculty of Pharmacy, 3Research & Development,
Alkaloid AD, 4Faculty of Natural Sciences and Mathematics

1 IEEE EUROCON 2017, 68 JULY 2017, OHRID, R. MACEDONIA

Morphine

Most used opioid analgesic drug

Recommended by the World Health Organization
Problems associated with the conventional oral
drug dosage forms
Development of modified release morphine
formulations

2 IEEE EUROCON 2017, 68 JULY 2017, OHRID, R. MACEDONIA

The Goal

Classical forms of morphine

morphine sulphate pentahydrate
morphine hydrochloride

Vibrational spectroscopic properties of solid-phase

morphine sulphate pentahydrate
Experimental studies: Fourier Transform infrared
spectroscopy
Theoretical studies: quantum chemical
computational technique based on meta hybrid
density functional theory approach
3 IEEE EUROCON 2017, 68 JULY 2017, OHRID, R. MACEDONIA
Computational Details -
General Theoretical Methodology

Potential energy surface (PES) of morphine

molecule, as well as of the N-protonated morphine-
H+
Geometry optimizations employing hybrid meta
density functional theory
Harmonic vibrational analyses (Computation and
sequential diagonalization Hessians matrices
enabled calculations of harmonic vibrational
frequencies )
Absence of imaginary frequencies true minimum

4 IEEE EUROCON 2017, 68 JULY 2017, OHRID, R. MACEDONIA

Hybrid Meta Density Functional
Theory Approach

Hybrid meta exchange- correlation functional M06-

2X
The Kohn-Sham (KS) SCF equations were solved
iteratively (99,590) grid for numerical integration

Calculations were performed with the Gaussian09

series of programs
5 IEEE EUROCON 2017, 68 JULY 2017, OHRID, R. MACEDONIA
Experimental Approach

FT-IR spectra recorded using the attenuated total

reflection method on a Varian 660 FT-IR
spectrometer
Spectra recorded at room temperature, using
MIRACLE ATR module with low-pressure
micrometer clamp
16 spectra accumulated and averaged

6 IEEE EUROCON 2017, 68 JULY 2017, OHRID, R. MACEDONIA

Results Structure and Energetics
(1)

The structures
corresponding to real
minima located on the
M06-2X/6-311G(d,p)
PES of free morphine
molecule

7 IEEE EUROCON 2017, 68 JULY 2017, OHRID, R. MACEDONIA

Results Structure and Energetics
(2)

The structures
corresponding to real
minima located on the
M06-2X/6-311G(d,p)
PES of N-protonated
morphine-H+ molecule

8 IEEE EUROCON 2017, 68 JULY 2017, OHRID, R. MACEDONIA

Results - Vibrational Spectroscopic
Properties - Theory

Theoretical infrared spectra computed for the four

conformers of the free neutral morphine molecule
and the N-protonated morphine-H+ cation at the
M06-2X/6-311G(d,p) level of theory

9 IEEE EUROCON 2017, 68 JULY 2017, OHRID, R. MACEDONIA

Results - Vibrational Spectroscopic
Properties - Experiment

Experimental FT-IR spectra of a solid state sample

of morphine sulphate pentahydrate
Complete (as-recorded) absorption spectrum -left
Generated by eliminating the regions with notable
contributions from the anionic (supposedly
hydrogensulphate) species, and rescaling the
ordinate axis -right
10 IEEE EUROCON 2017, 68 JULY 2017, OHRID, R. MACEDONIA
Vibrational Spectroscopic
Properties

The highest frequency region of the spectrum

contains bands due to X-H vibrational modes
Inspection of the spectral pattern in the region
above 2000 cm-1 indicates a specific sequence of
bands with a sharp Evans hole
Direct comparison between theory and experiment
is unfortunately hampered in the case of this
spectral region

11 IEEE EUROCON 2017, 68 JULY 2017, OHRID, R. MACEDONIA

Inspection of the experimental
spectra

Stretching Regions Bands

C-C ~ 1650 to 1450
cm-1
C-H, N-H (morphine 1500 1200
H+) and O-H cm-1
C-O around 1120 cm-
1

C-N (masked with the at ~ 1060 cm-1

symmetric S-O
stretching mode)
C-C ~ 1040 cm-1 to
1000 cm-1
CH3-N ~ 980 cm-1
C-H, S-O deformations Below 720 cm-1
12 IEEE EUROCON 2017, 68 JULY 2017, OHRID, R. MACEDONIA
Conlcusions

Combined FT-IR spectroscopic and theoretical

study of morphine sulphate pentahydrate
Hydrogen sulphate anionic species present in the
investigated solid state system
Solid phase contains both neutral morphine
molecule and N-protonated morphine-H
Theoretical results are in remarkable agreement
with the experiment

13 IEEE EUROCON 2017, 68 JULY 2017, OHRID, R. MACEDONIA

Future directions

Further spectroscopic study of other morphine

formulations especially in the context of its
incorporation into specific drug dosage forms

14 IEEE EUROCON 2017, 68 JULY 2017, OHRID, R. MACEDONIA