Departement of Pharmaceutics and Pharmaceutical Technology, Universitas Padjadjaran, Jatinangor 45363

Received : 2 May 2020/Revised : 12 May 2020/Accepted : 17 May 2020/ Published:23 Jun 2020

Solubility as a cause of ineffective active pharmaceutical ingredients (API) needs to be a

concern. One of the solutions to increase the solubility by choosing active ingredients in the

amorphous form. However, the amorphous form tends to be unstable because it has high Gibbs

free energy and molecular mobility. To overcome those properties solid dispersion methods can

be an answer. The dispersion of the amorphous form in the polymer is expected to prevent the

transformation of API to crystal stable form. The solid dispersion (SD) resulted needs for

DSC – Differential scanning calorimetry

FTIR – Fourier transform infrared

HSPLM – Hot stage polarization light microscopy

PLM – Polarization light microscopy

SEM – Scanning electron microscopy

ssNMR – Solid state nuclear magnetic resonance

TGA – Thermogravimetric analysis

TMDSC – Temperature modulated differential scanning calorimetry

polymorphism (2), crystallinity (3), particle size (4),

pKa (1), dielectric constant, and polarity (5). One

that, the amorphous form is unstable and tends to

Initial selected article (n = 97)

69 articles selected after initial screening

suspended into a polymer solution producing a

heterogeneous (16). The preparation based on the

characteristic of API material. Well known

characteristic of API are essential to achieve

successful ASDs. For example, the spray drying

preparation is used for API that are soluble in

volatile solvents (17), a co-precipitation method is

used for API with high melting points and low

solubility in organic solvents. For API with high

melting points, the hot melt extrusion is used instead

Based on Table 1, the hot melt extrusion

preparation is the most widely used method. The

absence of organic solvent yields a result without

residue. This method involves mixing, melting, and

homogenizing which can be applied on an industrial

scale. For example, oleanolic acid prepared using hot

melt extrusion using PVP VA64, shows a dissolution

rate of 90% in 10 minutes (18). Also, efavirenz

methods are needed to investigate the amorphous

Raman) to analyze the interaction of component

molecules, and XRD to analyze changes in

crystallinity as presented in Table 2. The

characterization method used in ASDs. Each

characterization method will support each other to

aid the investigation of amorphous forms in solid

dispersions. The next section will discuss the

interpretation of result of characterization.

details based on spectroscopic techniques,

relaxometry, and structural images (33). Its main

purpose is to identify the structure and

transformation of solids. The prediction made by

ssNMR regarding the domain size between the drug

and the polymer by correlating the relaxation time

with the round diffusion length scale (34).

Foster et al., comparing Nifedipine and

indomethacin ASDs mobility using

H NMR. The

et al. uses

C NMR against cyclosporine ASDs –

αβ-Cyclodextrins, cyclosporine crystal spectrum

with alkyl C-C peak chemical intensity between 30

and 10, N-C = O at 174 – 170; C = O at 130 – 120;

C-OH at 75 – 70; and N at 60 – 50 ppm were

changed after being on a solid dispersion system. C-

C alkyl intensity significantly changes with the

occurrence of chemical shifts. It signifies the

interaction of cyclosporine-αβ-cyclodextrins

morphology, particle size and crystallinity of the

sample (37). Characterization of ASDs generally

uses polarized light microscopy (PLM) because it

can detect crystals or amorphous. Amorphous solids

are isotropic, which means the molecules are

randomly oriented. As a result, amorphous solids do

not have double refraction, are nonbirefringent, and

do not show color interference. Meanwhile,

crystalline solids are anisoptric whose molecules are

arranged in a regular order, have color interference

al. by the lightly grinding method, which is between

dutasteride-polymer (Kollicoat

MAE 100P,

Soluplus

F68, and Kollidon

Microscopic observations were made to see the

solubility of the dutasteride dispersed in a polymer

(Fig. 3). It was assumed that the higher the sample

clarity from the PLM results then it also had the

higher solubility capacity. Based on PLM results,

dutasteride - Kollicoat

solubility (39).

resulting polarization images show the presence of

microcrystals birefringence that was not previously

detected by DSC and XRD. It should be noted that

the presence of microcrystals is also influenced by

the ratio between API-polymers. Based on this, PLM

is a more sensitive method compared to XRD and

DSC for analyzing crystal growth (54).

and after melting perfectly. HSPLM provides

information that the transformation of crystal form

into amorphous form (15).

SEM has been widely used in the pharmaceutical

field to develop and control the quality of materials

and dose. The main purpose of using SEM is to

analyze the morphology of the sample, particle size,

and formulation so that it can be used to analyze

ASDs. Quantitative analysis can also be obtained

energy. Whereas non-elastic collision does not

change direction, but transfers the electrons to the

specimen (56).

to analyze celecoxib-PVP K30 ASDs. The used

diffraction peak indicates the crystalline molecule,

on amorphous manufacturing methods, i.e. the

method of melt quenching, spray drying, freeze

drying, and dehydration of trehalose dihydrate. The

materials affected by temperature. Information that

can be obtained, such as glass transition (T

at peak on 302.1 °C (Fig. 6).

increase T

amorphous molecules as well as inhibit the

crystallization process.

TGA is generally combined with other methods,

such as DSC and FTIR. In the characterization of

ASDs, TGA is used to determine thermal stability,

changes in material weight affected by temperature,

5.69%, while the dispersion system experienced an

weight loss of 1.87%, which is the percentage of

evaporation of water that depends on relative

not provide specific information regarding the state

of the amorphous form in solid dispersions.

demonstrated its success in overcoming the

solubility of poorly water soluble drugs and the

method of solid dispersion in maintaining

amorphous stability. Therefore, the FDA has

approved several ASDs products that have been

circulating in the market, among which are presented