الفهرس 
Biopharmaceutical classification system (BCS)
mproving the dissolution rate of drugs by prodrugOnly 14 pages are availabe for public view
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Abstract
Amiodarone is one of the world’s most common antiarrhythmic
medicines. It is a derivative of benzofuran, used for the treatment of both
supraventricular and ventricular arrhythmias. The bioavailability of
Amiodarone is low due to its poor water solubility because it is classified
as a compound of class II drugs, which are low water soluble and highly
permeable by biopharmaceutical classification system.
Various technological techniques for improving solubility and
dissolution rate of low water-soluble drugs have been recorded. Coprocessing
with hydrophilic carriers increases the dissolution rate due to
reduced particle size and the micro-level interaction between drug
and carrier. Co-grinding affects physical characteristics of drugs such as
the surface area, crystal structure and shape. It is an environmentally
friendly solvent-free method that may be employed in large doses of APIs
with variable levels of solubility. It is simple, cost-effective and quick,
with simple equipment that can be readily expanded for business use. The
objective of this research was to create a single step, solvent-free method
to improve the dissolution of low water-soluble drugs.
The objective of this work was to prepare and assess rapidly
disintegrating amiodarone tablets after increasing the dissolution rate of
Abstract
Pharmaceutical Technology department, College of Pharmacy, University of Tanta, Tanta, Egypt. XIII
the drug. For this purpose, mechanochemical technique was applied by
co-grinding the drug with sugar excipients (mannitol and xylitol) that
impart good taste to the tablets in addition to its potential for forming cocrystal
with the drug with the aim to improve its dissolution. Possible cocrystal
formation will be evaluated by solid state characterization.
Additionally, co-grinding with salt forming excipient (benzoic acid) will
also be investigated. The selection of these excipients based on the
reported ability to modify the crystalline structure of many drugs after coprocessing.
Preparation of amiodarone co-processed formulations
Solid state grinding, or also called dry co-grinding, was used for
the preparation of amiodarone formulations. Amiodarone and the selected
excipient, at Different molar ratios were dry grinded for 30 minutes using
mortar and pestle. The obtained powder samples were stored in air-tight
containers till use. To evaluate the effect of grinding technique, Pure
Amiodarone and excipients were similarly treated, with the former taken
as positive control.
Physical characterization of the prepared formulations
FTIR spectroscopy was conducted to amiodarone, pure excipients
and selected formulations. Regarding the co-processed mixtures of the
Abstract
Pharmaceutical Technology department, College of Pharmacy, University of Tanta, Tanta, Egypt. XIV
drug with either xylitol or mannitol, the main characteristic peaks of both
materials and the drug can be detected. This suggested no interaction
between the drug and the used sugar excipients. Co-processed mixture of
benzoic acid and amiodarone showed a compromised spectrum. The peak
for carbonyl group of the drug was reduced in intensity and slightly
shifted to a lower wave length. Meantime, the broad peak for the
carboxylic OH group was reduced and became more broader. This
suggested interaction between the basic amiodarone and the acidic
excipient.
The thermal behavior of Amiodarone, pure excipients and their cogrinded
formulations were also monitored. The thermogram of coprocessed
drug with either xylitol or mannitol revealed peaks broadening
and shifting to lower temperatures. The main peak of amiodarone in the
binary mixtures reduced to lower Tm values. This indicates partial
amorphousization of the drug. This was accompanied by broadening of
the decomposition peak of the sugar and shifting to lower Tm value. For
benzoic acid co-processed mixtures both the endothermic peaks of
amiodarone and the co-former disappeared and new peaks were detected.
This may suggest formation of new species, most probably salt form.
The crystalline nature of unprocessed amiodarone, pure excipients
and different formulations were investigated using PXRD. The X-ray
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Pharmaceutical Technology department, College of Pharmacy, University of Tanta, Tanta, Egypt. XV
spectra of co-grinded drug with either xylitol or mannitol showed the sum
of the diffraction peaks for sugars as well as the drug. This indicated no
interaction between the drug and the excipients and confirms the results
of the DSC. This support the results of FTIR and DSC. For co-processed
drug with benzoic acid produced crystalline materials having slight
compromised X-ray diffraction pattern compared with that of the
individual components of the co-ground mixture. The appearance of new
diffraction peaks would indicate formation of new species. This result
coincides with the DSC data that suggested salt formation between the
drug and the additive.
Dissolution studies of the prepared formulations
The dissolution profiles of pure unprocessed amiodarone reflected
its poor dissolution behavior as indicated from the Q5 and DE
(percentage dissolved after 5 minutes and dissolution efficiency).
However, there was a slight improvement in dissolution for the positive
control (grinded drug alone) most probably due to particle size reduction.
As our aim was to formulate rapidly dissolving tablets of amiodarone, a
prompt initial release was important. Therefore, amiodarone was coground
with inert materials expected to produce co-crystal with the drug
while maintaining their function as excipients used in formulating fast
disintegrating tablets (i.e. sweetening agents). Xylitol and mannitol were
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Pharmaceutical Technology department, College of Pharmacy, University of Tanta, Tanta, Egypt. XVI
used for this purpose. Additionally, benzoic acid was also used as
potential salt forming excipients. For drug:xylitol co-processed mixtures
the enhancement in dissolution parameters increased by increasing xylitol
content in the formula. The improved dissolution of drug after neat
grinding with xylitol could be due to the reduced particle size, as shown
by X-ray data. Partial amorphousization, as reflected by DSC results, and
possible adsorption of drug over the excipient surface should be taken
into account. Mechanochemical treatment of the drug with mannitol
markedly increased drug dissolution compared to either negative or
positive control. The reason for the obtained results can be explained as
for xylitol. For Benzoic acid-amiodarone co-grinded mixtures, the
dissolution profiles indicated improved dissolution of amiodarone relative
to unprocessed drug, as well as positive control. In addition to the above
mentioned reasons for the enhancement of drug dissolution after neat cogrinding
with xylitol and mannitol, such improvement could be due to
salt formation. This salt was a result of possible interaction between the
amine group of amiodarone and the carboxylic group of benzoic acid.