Elsevier

Analytica Chimica Acta

Volume 685, Issue 1, 24 January 2011, Pages 91-102
Analytica Chimica Acta

Automatic twin vessel recrystallizer. Effective purification of acetaminophen by successive automatic recrystallization and absolute determination of purity by DSC

https://doi.org/10.1016/j.aca.2010.11.011Get rights and content

Abstract

I describe an interchangeable twin vessel (J, N) automatic glass recrystallizer that eliminates the time-consuming recovery and recycling of crystals for repeated recrystallization. The sample goes in the dissolution vessel J containing a magnetic stir-bar K; J is clamped to the upper joint H of recrystallizer body D. Empty crystallization vessel N is clamped to the lower joint M. Pure solvent is delivered to the dissolution vessel and the crystallization vessel via the head of the condenser A. Crystallization vessel is heated (P). The dissolution reservoir is stirred and heated by the solvent vapor (F). Continuous outflow of filtrate E out of J keeps N at a stable boiling temperature. This results in efficient dissolution, evaporation and separation of pure crystals Q. Pure solvent in the dissolution reservoir is recovered by suction. Empty dissolution and crystallization vessels are detached. Stirrer magnet is transferred to the crystallization vessel and the role of the vessels are then reversed. Evacuating mother liquor out of the upper twin vessel, the apparatus unit is ready for the next automatic recrystallization by refilling twin vessels with pure solvent. We show successive automatic recrystallization of acetaminophen from diethyl ether obtaining acetaminophen of higher melting temperatures than USP and JP reference standards by 8× automatic recrystallization, 96% yield at each stage. Also, I demonstrate a novel approach to the determination of absolute purity by combining the successive automatic recrystallization with differential scanning calorimetry (DSC) measurement requiring no reference standards. This involves the measurement of the criterial melting temperature T0 corresponding to the 100% pure material and quantitative ΔT in DSC based on the van’t Hoff law of melting point depression. The purity of six commercial acetaminophen samples and reference standards and an eight times recrystallized product evaluated were 98.8 mol%, 97.9 mol%, 99.1 mol%, 98.3 mol%, 98.4 mol%, 98.5 mol% and 99.3 mol% respectively.

Introduction

Recent rapid advances in instrumental analysis have accentuated the need for analytical reference standards. To meet this requirement, a unique automatic recrystallization system for preparing highly pure crystals was proposed [1], [2], [3], [4]. Highly pure phenacetins were obtained from water at high recoveries (98% yield for each recrystallization) by five and seven times repeated automatic recrystallization. The melting points of these products were respectively equal to and higher than that of phenacetin reference standard of National Institute of Hygienic Sciences of Japan [2]. Prednisolone was recrystallized six times from acetone–hexane (1:1, azeotropic) mixture at 96% yield for each recrystallization. The melting point of this purified prednisolone was 4.1 °C higher than Japanese pharmacopoeia (JP) reference standard prednisolone and 6.6 °C higher than the JP grade one material. The purity of this prednisolone evaluated was above 99.98% by thin-layer chromatography and 99.9% by differential scanning calorimetry (DSC) [3]. Curcumin was also highly purified from diethyl ether at 93% yield for each recrystallization by the technique. The purity of two commercial curcumin samples and a six times recrystallized product determined was 87.0 mol%, 91.2 mol%, and 99.6 mol% respectively by DSC [4].

A novel approach to the determination of absolute purity by repeated purifications with the automatic recrystallization method was proposed [5]. A unique method for purity determination requiring no reference standards was developed and theoretical considerations were presented. This involves the measurement of spectrophotometric molar absorptivities of consecutively recrystallized samples and extrapolating the absorptivity to obtain ɛ, corresponding to the 100% pure material. Purity is then determined by the ratio ɛs/ɛ, where ɛs is the absorptivity of the impure sample. Several experimental measurements for ellagic acid are presented. The purity of two commercial ellagic acid samples and a four times recrystallized product evaluated were 97.7%, 98.1%, and 100.1% respectively. The proposed approach should be valuable for quality control where preparation of highly pure crystals or reference standards are necessary.

The automatic recrystallization technique enables facile repeated recrystallization. The above experience with this instrument reveals, however, the requirement of cumbersome manual procedures that the separated crystals have to be recovered from mother liquor in the crystallization flask and transferred to the dissolution reservoir for every repeated recrystallization.

In the present paper, a novel interchangeable twin vessel automatic Pyrex recrystallizer that eliminates the time-consuming recovery and recycling of crystals for repeated recrystallization and should play an invaluable role in preparing highly pure crystals, has been proposed. Also, a novel approach to determine absolute purity by repeated purifications with an automatic recrystallization method and DSC measurement requiring no reference standards is proposed here.

Section snippets

Instrument and procedure

Fig. 1 shows the automatic glass recrystallizer unit, which has novel interchangeable twin vessels (J, N) containing a filter paper cylinder (E) over the dissolution reservoir (J). O-ring sealed detachable precision joints are used at C, H and M to achieve an organic solvent leak-free system. A filter paper cylinder (E) is firmly placed in the socket (G) with a plug (I) on which the cylinder has been placed. The impure sample is directly weighed in the dissolution vessel (J) containing a

Efficient repeated automatic recrystallization of acetaminophen

Source A commercial acetaminophen was easily recrystallized eight times from diethyl ether. The solubilities of acetaminophen in diethyl ether at room temperature averaged 1.23 g L−1. Recoveries were on an average 96% for each recrystallization.

Operational problems of previous automatic laboratory recrystallizers were solved here. Simply by reversing the role of the twin vessels to repeat the recrystallization each time, this new recrystallizer dramatically eliminates the time-consuming

Conclusions

We have developed a novel automatic recrystallizer with full considerations of underlying precipitation/crystallization mechanism. The present technique offers significant advantages over existing methods of recrystallization. The ease and reliability of the unattended automatic recrystallization operations and the ideal purification conditions for preparing highly pure crystals make this attractive.

A novel way of combining the successive automatic recrystallization with DSC measurement to

Acknowledgements

I am greatly indebted to Tsutomu Sato of Sato Seisakusho Corporation, for constructing the prototype by molding out the o-ring installed precision joints. I also deeply thank P.K. “Sandy” Dasgupta of University of Texas at Arlington for his fruitful comments and scrupulous reviews.

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