- *Corresponding Author:
- A. Ravikiran

Department of Chemistry, SRM University, SRM Nagar, Kattankulathur-603 203, Kancheepuram, India

**E-mail:**[email protected]

Date of Submission | 16 January 2013 |

Date of Revision | 07 April 2013 |

Date of Acceptance | 12 April 2013 |

Indian J Pharm Sci 2013; 75(3):361-364 |

## Abstract

In the current work the kinetics of dehydration of ziprasidone hydrochloride monohydrate was studied by nonisothermal thermogravimetry. Ziprasidone hydrochloride monohydrate was heated from 30 to 150° with a heating rate of 5° per min under nitrogen gas atmosphere and weight loss data were collected. Powder X-ray difraction was used to characterize the solid before and after dehydration. The well accepted Coats-Redfern model fitting approach was applied to the thermogravimetry data for the kinetic analysis. Thirteen solid state reaction models were studied; among them one-dimensional diffusion model was found to be the best fit model for this reaction with an excellent correlation 0.9994. The Arrhenius parameters, activation energy, and pre-exponential factor were determined, the values were found to be 28 k.cal/mol and 9.53×10 13 sec−1 , respectively.

## Keywords

Model fitting, kinetics, dehydration, thermogravimetry, ziprasidone hydrochloride

Ziprasidone hydrochloride (ZH), chemically
5-[2-[4-(1,2benzisothiazol-3-yl)-1-piperazinyl]
ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one,
monohydrochloride, represented in **fig. 1**, is a
typical antipsychotic drug used for the treatment of
schizophrenia, a mental disorder. It is commercially
available as Geodon^{®} capsules[1]. Anhydrous and
monohydrate forms of ZH are known from literature[2].

In view of increasing regulatory concern related to
solid form of the drug substance in the recent days,
it is highly important to understand the physical
stability of different solid forms of a drug substance
and their inter-convertibility[3,4]. Understanding
the kinetics of solid state reactions in relation to phase transformations of drug substance leaves an
opportunity to optimize the operational conditions
so as to prevent and have control over the changes
in solid from, during manufacturing process and
shelf life of the drug product. In the present work
dehydration of ZH monohydrate to ZH anhydrous
form, as represented in Eqn. (1) was studied by
thermogravimetry (TG). ZH.H_{2}O→ZH+H_{2}O.(1) TG is often used to study the kinetics of solid
state reactions involving weight change during
reaction. Some examples of such reactions include
thermal decomposition, oxidation, and dehydration
or desolvation[5,6]. Since the number of data points is
high enough for kinetic analysis of weight loss data,
TG has become useful for this purpose. In the present
work TA’s Thermo gravimetric analyzer (TGA),
Model Q5000IR was used for the study. Temperature
calibration of TGA was performed by measuring
Nickel Curie point (CP) at 354°. The Curie point is
a physical property of a metal; it is the temperature
point above which the metal loses ferromagnetic
properties. Weight calibration of TGA was performed
by using 50 mg standard reference material. About
15.7 mg of ZH-monohydrate was taken into aluminum
pan. The instrument was programmed to heat the
specimen from 30 to 150° with a heating rate 5°
per min. Nitrogen was used as a purge gas with a
flow rate of 50 ml/min. Model fitting approach[7-9]
was applied on the collected weight loss data
using Coats-Redfern method[10]. Powder X-Ray
diffraction (PXRD) patterns of the ZH-Anhydrous and
ZH-Monohydrate were collected by using Bruker D8
ADVANCE Powder X-ray Diffractometer equipped
with Cu anode.

General form of rate equation of solid state reactions
used for isothermal analysis is where α is the extent of reaction, t is the time, T is
the temperature, and f (α) is reaction model. For the
current dehydration study: where w_{o},
wt and B are the initial mass of the sample, the mass
at time t and the fraction of weight loss for complete
dehydration of the reaction, respectively. Integral form
of Eqn. (2) is According to Arrhenius equation ….(5), where k, Ea, and A are the rate constant,
the activation energy, and the pre-exponential
factor, respectively. under
nonisothermal conditions integral form of Eqn. (6) is where b is the heating rate. is replaced by a variable x, the temperature
integral Eqn. (7) becomes then the Eqn. (8) becomes where, p(x) is the
exponential integral, it has no analytical solutions but
has many approximations[11]. The Eqn. (9) can be used
for several model fitting methods for the analysis of
nonisothermal kinetics.

Model-fitting approach involves fitting different models to α-temperature curves. A model is a mathematical expression, developed based on mechanistic assumptions, transforms a solid state reaction process into a rate equation. Therefore, different rate expressions are produced from these models. To explain solid state reactions, there are four models such as (i) nucleation, (ii) geometrical contraction, (iii) diffusion, and (iv) reaction order models. Briefly, nucleation model is often used for reactions like crystallization, crystallographic transition, decomposition, adsorption hydration, and desolvation. The geometrical contraction model assumes that nucleation occurs rapidly on the surface of the crystal and the rate of degradation is controlled by the resulting reaction interface progress toward the center of the crystal. The diffusion model best explains solid state reactions involving gaseous products, where the reaction rate is controlled by the movement of reactants or products from the reaction interface or product layer. The order-based models are the simplest models as they are similar to those used in homogeneous kinetics. In these models, the reaction rate is proportional to concentration, amount or fraction remaining of reactant(s) raised to a particular power (integral or fractional) which is the reaction order[12].

In the current study popular Coats-Redfern method
was used in which the asymptotic series expansion for
approximating Eqn. (9) is used to get the following
equation: where T is the mean experimental temperature. Using
this Eqn. (10), the values of E_{a} and A can be obtained
from slope and intercept values, respectively, from the graph plotted for versus 1/T for different
models, as represented in **Table 1**.

Reaction model | f(α) |
g(α) |
Ea (kcal/mol) |
A |
-R |
---|---|---|---|---|---|

Nucleation models | |||||

Power law | 4α3/4 | α1/4 | 2 | 0.01 | 0.9988 |

Power law | 3α2/3 | α1/3 | 4 | 0.03 | 0.9990 |

Power law | 2α1/2 | α1/2 | 0 | 0.00 | 0.9945 |

Avrami-Erofeev | 4 (1-α) [-ln (1-α)]^{3/4} |
[-ln (1-α)]^{1/4} |
3 | 0.01 | 0.9956 |

Avrami-Erofeev | 3 (1-α) [-ln (1-α)]^{2/3} |
[-ln (1-α)]^{1/3} |
4 | 0.12 | 0.9963 |

Avrami-Erofeev | 2 (1-α) [-ln (1-α)]^{1/2} |
[-ln (1-α)]^{1/2} |
7 | 9.18 | 0.9969 |

Diffusion models | |||||

One dimensional diffusion | 1/2 α-1 | α2 | 28 | 9.53×10^{13} |
0.9994 |

Diffusion control (Janders) | 2 (1-α)^{2/3} [1-(1-α)^{1/3}]^{-1} |
[1-(1-α)^{1/3}]^{2} |
31 | 1.47×10^{15} |
0.9983 |

Diffusion control (Crank) | 3/2[(1-α)-^{1/3}-1]^{-1} |
1-2/3 α-(1-α)^{2/3} |
30 | 2.66×10^{14} |
0.9987 |

Reaction order and geometrical contraction models | |||||

Mampel (first order) | 1-α | [-ln (1-α)] | 16 | 3.06×10^{6} |
0.9974 |

Second Order | (1-α)^{2} |
(1-α)^{-1}-1 |
18 | 2.20×10^{8} |
0.9944 |

Contracting cylinder | 2 (1-α)^{1/2} |
1-(1-α)^{1/2} |
14 | 2.12×10^{5} |
0.9985 |

Contracting Sphere | 3 (1-α)^{2/3} |
1-(1-α)^{1/3} |
15 | 2.70×10^{5} |
0.9981 |

**Table 1:** Solid state reaction models used and arrhenius parameters for nonisothermal dehydration of ziprasidone hydrochloride monohydrate using coats-redfern method

The TG data indicated a total weight loss of about
4.067% w/w in the temperature range from about 30 to 90° and it was also observed that the fraction
of extent of reaction was reached 0.5 at about 73°.
The TG thermogram is represented in **fig. 2**. The
comparison of PXRD patterns of ZH-anhydrous and
ZH-monohydrate is represented in **fig. 3**, which shows
the change in the PXRD profile of ZH-monohydrate
after dehydration process, indicating conversion of
the monohydrate into an anhydrous form, having a
different crystalline structure.

By using various expressions for g(α ) in Eqn. (10),
Arrhenius parameters were calculated from the plot of against 1/T. The set of calculated Arrhenius
parameters for dehydration of ZH monohydrate are listed in **Table 1**. For each model, goodness fit was
determined by the correlation value, as mentioned in
**Table 1**. All models have resultant correlation greater
than 0.99. The first six reaction models have very
small values of pre-exponential factor demonstrating
that these models cannot explain the reaction kinetics.
Among the remaining models, one-dimensional
diffusion model has got maximum correlation of
0.9994.

In conclusion, dehydration of ZH-monohydrate was
successfully studied using TG and PXRD. A distinct
Powder XRD pattern was observed for dehydrated
solid when compared with the monohydrate,
indicating transformation into different crystalline phase. The nonisothermal weight loss data obtained
from TG were used for kinetics analysis, one
dimensional diffusion model was found to be the best
fit among 13 models evaluated using Coats-Redfern
method and the calculated values of Ea and A
are 28 kcal/mol and 9.53×10^{13} sec^{−1}, respectively.
Thus, reliable evaluation of kinetic parameters of
dehydration process of pharmaceutical hydrates is
very important to optimize the operating conditions
required during manufacturing process and shelf-life
of its formulation. TG in combination with powder
XRD can be used to evaluate dehydration kinetics
and to determine Arrhenius parameters, in relatively
short time.

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