Table of Contents Author Guidelines Submit a Manuscript
Research Letters in Physical Chemistry
Volume 2008 (2008), Article ID 169247, 4 pages
Research Letter

The Cold Contact Method as a Simple Drug Interaction Detection System

1Pharmaceutics Laboratory, School of Pharmacy, Bandung Institute of Technology, Bandung 40132, Indonesia
2Chemical Pharmacy and Microbiology Laboratory, School of Pharmacy, Bandung Institute of Technology, Bandung 40132, Indonesia

Received 14 November 2007; Accepted 2 January 2008

Academic Editor: Leif A. Eriksson

Copyright © 2008 Ilma Nugrahani et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


The physical interaction between 2 substances frequently occurs along the mixing and manufacturing of solid drug dosage forms. The physical interaction is generally based on coarrangement of crystal lattice of drug combination. The cold contact method has been developed as a simple technique to detect physical interaction between 2 drugs. This method is performed by observing new habits of cocrystal that appear on contact area of crystallization by polarization microscope and characterize this cocrystal behavior by melting point determination. Has been evaluated by DSC, this method is proved suitable to identify eutecticum interaction of pseudoephedrine HCl-acetaminophen, peritecticum interaction of methampyrone-phenylbutazon, and solid solution interaction of amoxicillin-clavulanate, respectively.

1. Introduction

In the pharmaceutical area, investigation of physical interaction which is very possible to occur along the mixing manufacturing process of dosage forms is an important issue because a lot of physical properties of drugs especially in solid state dosage forms could be influenced. Such changes as stability, drug performance, dissolution profile, pharmacokinetics profile, and, moreover, the pharmacological effect should be much impacted by the interactions [13]. Physical interactions in the solid state dosage form frequently occur even in storage and distribution time of dosage forms [4, 5]. Therefore, the simple technique to detect the interaction might be very useful. Along last decades, Kofler’s hot stage contact method, which observed the co-recrystallization from 2 compounds from their hot molten state, has been used as a simple method to detect the cocrystal formation as an indicator for physical interaction occurrence [6]. Unfortunately, in pharmaceutical area, there are a lot of thermolabile compounds which cannot be crystallized after melting, because we have arranged a simple method used to detect physical interaction of the thermolabile compounds. This method was conducted by observing the process of cocrystallization and its behavior on crystallization contact area of 2 drugs from their solution under microscope polarization and melting point determination. Briefly, this method is developed from Kofler’s contact methods by changing the comelting technique to the cosolvating crystallization. Recently, we have investigated the cold contact suitability to detect and identify the physical interaction of 3 drug combinations which are usually found in the dosage forms. Acetaminophen-pseudoephedrine HCl is found in antiinfluenza dosage forms, methampyrone-phenylbutazon in analgesic dosage forms, while amoxicillin-clavulanate in antibiotic combination dosage forms. All of these combinations have brought some troubles in mixing and compounding which caused high variability on their dosage forms quality. We used the cold contact method to detect the possibility of physical interaction of these drug combinations and evaluated the method by differential scanning calorimeter (DSC) as a primary thermal analysis method.

2. Method and Results

The cocrystallization from solution in ambient temperature was suggested to be mentioned as the cold contact method [79]. In this report, differential scanning calorimeter (DSC) was used to evaluate the results by observing the thermal profile and arranging phase diagrams [1012]. From DSC data of varies molar or weight ratios (0 : 1, 1 : 9, 2 : 8, 3 : 7, 4 : 6, 5 : 5, 6 : 4, 7 : 3, 9 : 1, and 10 : 0), phase diagrams were arranged. In purpose to abbreviate the paper, phase diagrams are not presented.

The first drug combination which was examined is acetaminophen-pseudoephedrine HCl. Under polarization microscope, a black area was observed which melted at 113ºC, while pseudoephedrine HCl alone melted at 184ºC and acetaminophen alone at 170ºC (Figure 1(a)). It could be predicted that the binary system composed an eutectic mixture. By DSC, the prediction was evaluated and proved coherency. To clarify, the thermograms of 3 : 7, 5 : 5, and 7 : 3 weight ratios are described in Figure 1(b) which indicate the eutectic point at 112.3ºC, appropriate with cold contact data. Secondly, phenylbutazon-methampyrone combination showed a peritectic interaction which was proved by cold contact method and has been proven to be coherent with DSC analysis data. Last, amoxicillin-clavulanate mixture showed strong interaction with single exothermic transition curve at 202ºC, equal to its melting point which was observed by cold contact method.

Figure 1: (a) The cold contact area of acetaminophen-pseudoephedrine HCl corecrystallization showed an area which melted at (1) 113ºC, compared to the starting materials at (2) 170ºC and (3) 184ºC. (b) Thermograms of pseudoephedrine HCl showed melting point at 184.4ºC (top), acetaminophen at 169.5ºC (middle), and the eutectic mixture in weight ratios 5 : 5 at 112.3ºC (bottom).
Figure 2: (a) The contact area of methampyrone-phenylbutazon indicated peritecticum mixture: (1) before heating, (2) phenylbutazon melted at 105ºC, (3) contact area-1 melted at 119ºC, (4) contact area-2 melted at 140ºC, (5) contact area-3 melted at 150ºC, and (6) methampyron melted followed by oxidation at 220–230ºC. (b) DSC data of phenylbutazon (top), methampyrone (middle), and the mixture of methampyrone-phenybutazon 7 : 3 weight ratio.
Figure 3: (a) Cold contact observation results: (i) the cocrystal grew from clavulanate crystal to amoxicillin solution in NaOH, (ii) amoxicillin melted at 194ºC, clavulanate oxidized at 203ºC, while the cocrystal oxidized least. (b) DSC data of amoxicillin trihydrate (top), potassium clavulanate (middle), and the physical mixture 1 : 1 (bottom). The exothermic peak of 1 : 1 mixture shows that amoxicillin and clavulanate overlay and become 1 peak at 202ºC which indicates a solid solution interaction.
Figure 4: Cold contact preparation: (1) solution A dropped on clean object glass, (2) let it be crystallized, (3) then solution B dropped near the crystal A, (4) if it interacted, the new habit with different melting point will be formed on the contact area.

The results prove strong relation between cold contact method data and DSC. The simple eutectic interaction of pseudoephedrine hcl-acetaminophen, the peritectic interaction between methampyrone-phenylbutazon, and solid solution formation between amoxicillin trihydrate-clavulanate have been early detected by this simple method. Therefore, this method has high possibility to be used as a simple method to evaluate the other drug interactions [1013].

Briefly, the experiment could be performed as follows.

(i)Each of the components is dissolved in the same solvent. Drop the solution 1 on cleaned object glass, evaporate the solvent and let it crystallize. The second solution is dropped near the formed crystal, let it diffuse slowly toward the crystal then quickly evaporate the solvent. Let second crystallization be performed and observe the contact area.(ii)Heat the cold contact preparation on hot plate and observe the melting point. Differences of melting points indicate the cocrystallization or physical interaction.(iii)The observation result could be confirmed with DSC.

3. Conclusion

The acceptability of the cold contact method as a simple method to identify the physical interaction of drug combination has been proved by coherency between the cold contact method data with the DSC evaluation.


  1. G. Bettinetti, M. R. Caira, A. Callegari, and M. Merli, “Structure and solid-state chemistry of anhydrous and hydrated crystal forms of the trimethoprim-sulfamethoxypyridazine 1:1 molecular complex,” Journal of Pharmaceutical Sciences, vol. 89, no. 4, pp. 478–489, 2000. View at Publisher · View at Google Scholar
  2. M. R. Caira, “Sulfa drugs as model co-crystals former,” Molecular Pharmaceutics, vol. 4, no. 3, pp. 310–316, 2007. View at Publisher · View at Google Scholar · View at PubMed
  3. G. P. Stahly, “Diversity in single- and multiple-component crystals. The search for and prevalence of polymorphs and cocrystals,” Crystal Growth & Design, vol. 7, no. 6, pp. 1007–1026, 2007. View at Publisher · View at Google Scholar
  4. R. E. Davis, K. A. Lorimer, M. A. Wilkowski, and J. H. Rivers, “Studies of phase relationships in cocrystal systems,” Transaction of the American Crystallographic Association, vol. 39, pp. 41–61, 2004. View at Google Scholar
  5. N. Rodriguez-Hornedo, “Crystallization and the properties of crystals,” in Encyclopedia of Pharmaceutical Technology, J. Swarbrick and J. C. Boylan, Eds., vol. 3, pp. 399–434, Marcel Dekker, New York, NY, USA, 1990. View at Google Scholar
  6. Wikipedia, “Recrystallization,” 2007,
  7. I. Nugrahani, S. N. Soewandhi, S. Asyarie, and S. Ibrahim, “The cold contact methods to detect physical interaction of paracetamol-pseudoephedrine HCl,” Artocarpus, vol. 6, no. 1, pp. 18–29, 2007. View at Google Scholar
  8. I. Nugrahani, S. N. Soewandhi, S. Asyarie, and S. Ibrahim, “The cold contact method to detect physical interaction of amoxicillin-clavulanate,” in Proceeding of International Chemical Conference and Seminar, Yogyakarta, Indonesia, 2007.
  9. I. Nugrahani, S. N. Soewandhi, S. Asyarie, and S. Ibrahim, “Study of levodopa-benserazide interaction by cold contact method,” Indonesian Journal of Pharmaceutical Science, vol. 18, no. 2, 2007. View at Google Scholar
  10. S. R. Byrn, R. R. Pfeiffer, and J. G. Stowell, Solid State Chemistry of Drugs, SSCI, West Lafayette, Ind, USA, 2nd edition, 2000.
  11. J. T. Cartensen, Advanced Pharmaceutical Solids, Taylor & Francis, New York, NY, USA, 2001.
  12. F. Giordano and A. Rossi, “Phase diagrams in the binary system,” Bollettino Chimico Farmaceutico, vol. 139, no. 4, pp. 345–349, 2000. View at Google Scholar
  13. Drugbank, “Acetaminophen, Pseudoephedrine, Antalgine, Phenylbutazone, Amoxicillin, and Clavulanate,” March 2006,