EXPERIMENTAL AND DENSITY FUNCTIONAL THEORY INVESTIGATIONS ON THE

246 4.29 Parts of the geometry parameters (i.e. bond distances, bond angles and dihedral angles) of the TP-II molecular system. 4.30 (a) LUMO and HOMO surface maps of the TP-II molecular system using the DFT/B3LYP/6-31G method.

CONCLUSION

Ab-initio

Hartree-Fock (HF) Theory
Basis Set
Functionals

Local density approximation (LDA)
Generalised gradient approximation (GGA)
Hybrid functionals

In 1926 a great achievement is made by Erwin Schrödinger with the introduction of the Schrödinger wave equation. In the generalized gradient approximation (GGA) functional, the mathematical approach takes into account not only the electron density (as in LDA), but also the gradient of the electron density at each point (Köse, 2001).

Polymorphism

Formation of polymorphs
Characterization of polymorphs

Single Crystal X-ray Diffraction Analysis
Fourier Transform Infrared (FT-IR) Spectroscopy
Ultraviolet-Visible (UV-Vis) Spectroscopy

The instrument used in single crystal X-ray diffraction method is known as X-ray diffractometer. Each of the peaks in the FT-IR vibrational spectrum provides informative data about the types of functional groups presented in the target sample. Besides that, the intensity of the absorption peaks corresponds to the number of functional groups in the target sample, is also given by the analysis (Co., 2019).

It can be used to analyze the rate of reaction in chemical compounds based on the change in the concentration of chemical substances and the absorbance of UV-Vis radiation. This is because wavelengths below 200 nm (vacuum UV light) and above 800 nm (infrared light) show low practical utility in a UV-Vis spectroscopy experiment (Rocha et al., 2018). Below these ranges, only 𝑛 → 𝜋∗ and 𝜋 → 𝜋∗ types of electron transitions can be observed in the target sample.

As the target sample passes through the UV-Vis radiation beam, the decrease in the input UV radiation intensity (𝐼) at a particular wavelength indicates the absorption activities of the target sample.

Figure 2.1 (a): The single crystal X-ray diffractometer (Bond, 2016).

Active Pharmaceutical Ingredients (APIs)

Acyclovir (ACV)

According to the studies of Raza et al. 2014) and Karpinski (2006), most (more than 50%) of the active pharmaceutical ingredients (APIs) tend to form polymorphism easily. Consequently, the properties will affect the bioavailability, safety and therapeutic performance of the API drug compounds (Fucke et al., 2012). The state of hydration in drug formulations of APIs shows effects on the physical properties, pharmaceutical performance and processability of drugs (Chan et al., 2014).

In addition, the low transdermal absorption rate of ACV meant that it could not easily penetrate the skin (Yan et al., 2013). For example, Birnbaum et al. 1984) synthesized one of the monoclinic hydrated polymorphic forms of ACV from aqueous dimethylformamide. Moreover, in order to increase the solubility and permeability of the medicinal compound ACV, Yan et al. 2013) have successfully obtained three different salt and co-crystalline polymorphic forms of ACV using maleic acid, fumaric acid and glutaric acid.

Besides, with the aim of improving the physical stability of the TP drug compound, Aitipamula et al. 2009) have discovered a new triclinic co-crystal polymorphic form of TP through the crystallization technique of TP with gentisic acid and methanol.

Potential Energy Surface (PES)

The geometry optimization process would be complete and successful when a stationary point is found on the PES. A stationary point refers to the point where the force and gradient are equal to zero (Foresman and Frisch, 1996; Nyakung'U, 2015). In PES, the stationary point can be located at the global minima, local minima, and the saddle point.

Theoretically, a geometry optimization process is said to be complete when the force, the root-mean-square of the force, the next step-displacement, and the root-mean-square displacement all equal zero. Unfortunately, the practical values do not always reach exactly zero when it comes to the real geometry optimization process. Thus, several convergence criteria have been established by calculation software to determine the completeness of the geometry optimization calculation.

For example, in the Gaussian 09 software package, for any system that has a force below the cut-off value of 0.0005, force root-mean-square tolerance of 0.0003, next-step displacement below cut-off value of 0.0018, and displacement root-mean-square cut-off value of 0.001 is performed and optimization of the geometry to 0.0012. , 1996).

Molecular Orbital (MO)

Three of them (i.e. HOMO energy, LUMO energy and HOMO-LUMO energy gap) have significant features in the characterization and determination of chemical reactivity, kinetic stability, electronic and optical properties of a molecular system (Bahgat and Fraihat, 2015; Rahmani et al., 2018). For example, if a substance is said to have a narrow HOMO-LUMO energy gap, it will have low kinetic stability, high chemical reactivity, soft and more polarizable (Bahgat and Fraihat, 2015; Ceylan et al., 2016; Rajalakshmi and Nayak, 2017). The energy barrier of electrons can be obtained by electron affinity and ionization potential (Ceylan et al., 2016).

The ionization energy represents the amount of energy required to remove an electron from an occupied orbit, while the electron affinity measures the amount of energy lost when an electron is added to an empty orbit (Asath et al., 2017). Molecular electrostatic potential (MEP) refers to the interaction energy (𝑉(𝑟) ) between the molecular charge distributions with a unit positive test charge at a given point 𝑟 (Orozco and Luque, 1996; Alipour and Mohajeri, 2010; Drissi et al., 2015). The MEP visualizes the sites for electrophilic and nucleophilic reactions in a molecular system (Rahmani et al., 2018).

It has important applications in the prediction and study of catalysis process, biological recognition process and hydrogen bond interaction scheme (Ceylan et al., 2016; Kabouchi et al., 2017).

Natural Bond Orbital (NBO)

The blue color region represents the less negative (most positive) electrostatic potential region undergoing a nucleophilic reaction. On the other hand, the red color area represents the most negative (least positive) area where the electrophilic reaction will take place (shodhganga, 2021). The charge transfer interaction occurs through the overlap of occupied Lewis-type electron donor (bond or lone pair) NBO with unoccupied non-Lewis-type electron acceptor (anti-bond) NBO and caused stabilization in the molecular system (Balachandran et al., 2013; Dubey et al., 2018; shodhganga, 2021).

Higher in the stabilization energy reflects the fact that the donation tendency from electron donors to electron acceptors is greater and the extent of conjugation in the molecular system is greater (shodhganga, 2021). These result in stronger charge transfer interaction between electron donors and acceptors (Dubey et al., 2018).

Non-linear Optical (NLO) Properties

The powerful development of computational algorithms in quantum chemistry has made a significant contribution to the study of NLO properties. The NLO properties of a chemical compound can be obtained through studies of the dipole moment (𝜇0) and the first hyperpolarizability (𝛽𝑡𝑜𝑡 ). The dipole moment describes the fundamental property of a chemical compound based on the intermolecular interaction of the non-bonded dipole-dipole type (Rahmani et al., 2018).

It is useful in determining NLO properties in a molecular system (Ibeji et al., 2016). For the first hyperpolarizability, it is a 3rd rank tensor that can be presented by a 3 𝑥 3 𝑥 3 matrix. For example, the donor-acceptor mechanism, the nature of substitutes, the influence of flatness and the conjugated π system of a chemical compound (Raja et al., 2014).

To identify the NLO properties of a chemical compound, known NLO materials (i.e.

Flow of Research

Materials and Chemicals

Crystal Formation in Acyclovir (ACV) Drug Compound
Crystal Formation in Theophylline (TP) Drug Compound
Single Crystal X-ray Diffraction Experiment
Ultraviolet-Visible (UV-Vis) Analysis
Computational Method and Software
Input Source Preparation
Density Functional Theory (DFT) Computational Calculations

Geometry Optimization and Single Point Calculations
HOMO and LUMO Surface Mapped Plots
Molecular Electrostatic Potential (MEP) Surface Mapped Plots
Rotational Barrier Studies in ACV Molecules
Size Effect Studies of TP-I and TP-II Molecular System

The geometrical structures, electronic properties and vibrational frequencies of ACV and TP polymorphisms (i.e. ACV-I, ACV-II, ACV-III, TP-I, TP-II and TP-III) are obtained and discussed in this study. As a result, there were a total of six ACV and TP polymorphism compounds (i.e. ACV-I, ACV-II, ACV-III, TP-I, TP-II, and TP-III) included in DFT computational studies. During the geometry optimization calculations, the molecular geometry structures of ACV-I, ACV-II, ACV-III, TP-I, TP-II, and TP-III were specified using 𝑧 matrix (internal coordinates) approaches.

Equilibrium and stable molecular geometry optimized structures of ACV-I, ACV-II, ACV-III, TP-I, TP-II and TP-III were obtained and compared with experimental single crystal X-ray diffraction findings. After that, the reliable optimized geometry structures of ACV-I, ACV-II, ACV-III, TP-I, TP-II, and TP-III were used to perform fixed-geometry single-point calculations. Graphical interpretations of the HOMO and LUMO surface-mapped planes of the molecular system ACV-I, ACV-II, ACV-III, TP-I, TP-II and TP-III were drawn using the GaussView 5.0 software package.

The plots of molecular electrostatic potential (MEP) mapped from ACV-I, ACV-II, ACV-III, TP-I, TP-II and TP-III molecular system were generated using GaussView 5.0 software package.

Figure 3.2 (a): The heating process of the ACV mixture in Part A (deep blue

Molecular Geometry Structural Analysis
Total Energies and Frontier Molecular Orbital (FMO) Energies
Mulliken Population Analysis (MPA)
Molecular Electrostatic Potential (MEP)

Noticed that the crystal packing of ACV-I molecular system is stabilized by N-H.O and O-H.O types of intermolecular hydrogen bonding interactions (Sarojini et al., 2012). Furthermore, HOMO and LUMO 3D surface mapped plots of ACV-I molecular system are presented in Figure 4.3 (a) and (b). Previous literature studies have found that anhydrous ACV molecular system has HOMO-LUMO energy gap of 0.198 eV (Selsi et al., 2019).

Therefore, the experimental energy gap of the ACV-I molecular system can be obtained from the peak of the absorption spectrum. In addition, MEP also represents the molecular size, polarity and shape of the ACV-I molecular system. Thus, the possible regions are revealed where the intra- and intermolecular interaction of the ACV-I molecular system can take place (Sridevi, 2012; Kabouchi et al., 2017).

Noticed that the vector direction of the dipole moment in the ACV-I molecular system depends on the centers of positive and negative charges. In this work, the calculated FT-IR vibrational frequencies of the ACV-I molecular system are obtained using DFT/B3LYP/6-31G** and DFT/B3LYP/6-311G** level theories. Noted that there are no suspicious findings in the ACV-I molecular system FT-IR results.

Figure 4.1 (a): The complete unit cell of ACV-I.

Molecular Geometry Structural Analysis
Total Energies and Frontier Molecular Orbital (FMO) Energies
Mulliken Population Analysis (MPA)
Rotational Barrier Analysis

The diversity in the side chain orientations clearly indicates that ACV molecule A, B and C have independent geometry identities in the ACV-II molecular system. Based on the calculated HOMO and LUMO energies, the global descriptors of the ACV-II molecular system are obtained through the formulas stated in Koopmans' theorem. These indicate the presence of polarized C=O bonds in the ACV-II molecular system (Lakshmi et al., 2019).

Furthermore, Figure 4.12 (a) and (b) also illustrate the global surface extremes of the ACV-II molecular system calculated by the Multifwn software package. Both computational results clarify that the main contribution of the dipole moment in the ACV-II molecular system comes from the 𝑍 ( 𝜇𝑧) direction. It is worth noting that the ACV-II molecular system shows better active NLO nature than the ACV-I molecular system.

In conclusion, there are no suspicious findings in the computational FT-IR results of the ACV-II molecular system.