# The Cold Contact Method as a Simple Drug Interaction Detection System

Authors: Ilma Nugrahani; Sukmadjaja Asyarie; Sundani Nurono Soewandhi; Slamet Ibrahim
Journal: Research Letters in Physical Chemistry
 (2008)

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## Abstract

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.


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## Body

## 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 [1–3]. 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 thecold contact method [7–9]. In this report, differential scanning
calorimeter (DSC) was used to evaluate the results by observing the thermal
profile and arranging phase diagrams [10–12]. 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
(Figure1(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 [10–13].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.



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*Source: 169247-2008-02-19.xml*