Department of Organic

Chemistry and
Technology

Protocol

Practice: Laboratory practice of controlled crystallization

Date: 2019 - October 28.

Group: E3

Prepared by: Juan Santiago Hidalgo Viteri

Neptune Code: TE8NXD

Table of content

1. Short introduction, brief description of the measurements

2. Physical properties of the components
3. Pencil drawing of the apparatus
4. Measured data, measurement experiences, spectra, charts
5. Evaluations, conclusions

Checked by: Grade:

Remarks of the practice leader:

1. Introduction

Crystallization is a process to increase the purity of the products, consist in a procedure when
changing the concentration or the temperature you should increase the concentration of a product or
chemical component and separate these from another product or sub product that you do not want to
have in the final process.

In the whole process of crystallization nucleation and crystal growing are the two more important
steps, the first one consist in forming the nucleus of the crystal, it happens because the change in the
concentration of saturation of the product and the second one consist in increase the size and the
number of the products, for that is important to control the temperature and the concentration of the
products.

The most important application of crystallization is in the drug industry, in which almost all of the
products should be refined in order to achieve the maximum amount of purity, otherwise the drugs can
affect the organism and create some health problems in the human health, furthermore, more and more
applications are growing with the crystallization.

1.1. Brief description of the measurements

1.1.1. ATR - UV / vis

This spectroscopy technology is a useful technique to quantify solution concentration. Thus,

supersaturation control can be realized to ensure the proper product quality. The basic of
supersaturation control (SSC) is the real-time determination of solution concentration and
supersaturation value derived from inline detected concentration.

1.1.2. Procedure of the laboratory

 First measure 3.5 grams of carvedilol in an analytical balance taking care about the mas of the
product.
 After that measure 70 ml of ethyl acetate.
 When we have the two-measure substance, we make sure about the condition of the reactor,
first we should calibrate the temperature. For us the temperature was 25.4°C which was the
room temperature that day.
 In order to measure the conditions of the crystallization was important to set up the reactor, in
our case we choose the following characteristic: heating up the suspension to 65°C in a time
 interval of 10 min -isotherm period for 15 min to ensure complete dissolution -linear cooling
to 0°C in a time interval of 35 min (1°C/min cooling rate) meanwhile seeding the
supersaturated solution with 0.035 g seed crystals at 35°C.

 After these steps, we should introduce in the reactor first the carvedilol and after that we put
the ethyl acetate, for our case we should verify if every of the mass and the volume of the two
substance was not remained in the walls of the machine otherwise it can produce some
measurement problems during the calculation task.

 During the crystallization process the solution start to change the phase and the color, at the
begging was white but after the heating and the stirring the color change into cream and the
crystal start to appear. Furthermore, the viscosity and the crystal concentration start to change
after 30 minutes, it was necessary to add 3.5 grams of carvedilol + 70 ml of ethyl acetate to let
the crystal process growing increase.

 After 90 minutes we turn off the equipment and the sample were collected to follow the next
step.

 The final step was filtering the product using G2 glass filter and vacuum pump

2. Results

2.1. Process graphs

Fist of all it was necessary to evaluate the concentration time against the time of reaction, in the graph
number 1-1 we can see how the concentration change according with the time, it is a useful tool to
understand who the reaction occurs and how we can evaluate at what time is better to let the reaction
in order to purify the crystals.
Graph 1-1: Concentration vs time curve in the crystalization procces.

At the beginning of the procces we can observed a linear increase in the concentration that shows the start of the
reaction and the first formation of the crystal. After 20 minutes the change in the concentration is irregular and it
can explain some changes in the ratio of the crystal. Finally, after 60 minutes the concentration decreace uniform
that shows the final of the reactive procces.

One of the most important features in the crystalization procces is the temperature, for that it’s neccesary to
evaluate the change in the concentration and the heating period time. The first curve in the graph is the
sobresaturation curve which indicates the comportament of the crystalization part. In that we can observe the
change since 25°C until 50°C which consist in a linear increase after that it was a decreasing.

Graph 2-1: Concentration vs temperature in the crystalization procces.

Meanwhile in the crystallization evaluation in the graph we can observed how the temperature change
the properties of the crystals. At the beginning the crystals star the process of nucleation and if the
temperature increases the crystal growing process start. This process is not very controllable for that
reason the curve has some pics.

2.2. Calculation of Carr’s index and Hauser ratio

To calculate this index, we should use the following formula:

According with out date the results are:

 Carvedilol (4 h) linear cooling, first try

The table 1-2 shows the results about Carr’s index in the tree samples.
Table 1-2: Carr’s index in the tree samples.

As we can see the maximum results was reported by the Carvedilol + PVP K 90 with a carr’s Index
equal to 19% and the poor results was reported by the carvedilol after 4 hours with a result equal to
36.60%. In comparation with the two same samples changing the time of crystallization we can
change the features of the crystal and also, we can change the process of crystallization.

In comparation with the Carvedilol + PVP we can observe the change in the crystallization process if
we add another chemical product. Because this product achieve more saturation and it let the
nucleation and the crystal growing be better, for that reason some chemical products can change the
composition and purity of the crystals.

2.3. Comparison of POM images

To understand the behaviour and the form of the crystals it’s necessary to have a microscope look of
the structure; there we can obtain some perfect imagines about the inlet composition and the form of
the crystals and understand how the conditions in the experiments changes the conditions of the
crystals and how controlled the conditions of the forming crystals can be produce better results about
of sample.

The table 2-4 shows the differences between the three crystals. First of all, it’s important to compare
the two samples of carvedilol, in the first one we can observe very thin and small crystals distributed
around the sample. Instead of that, in the sample after 4 hours we can observe bigger and more
organizer crystals and more quantity of crystals. That is a proof of how the time affect the physical
structure of the crystals and how the crystal growing process behaves comparing with the time of the
process.

In the other hand, comparing the sample with carvedilol and the sample of carvedilol + PVP 90 K we
can observe how the chemical products affect the normal process of crystallization and it’s referred to
the saturation curve. The crystals in the third sample are hexagonal and very big it shows the stability
of the crystals.

Table 2-4: Microscope imagines of the three samples.

Carvedilol (4 hr) Carvedilol (1 h) Carvedilol + PVP 90 K

3. Conclusions

 ATR - UV / vis measure method allows to understand the crystallization process and allow to
control some of the characteristics in order to improve the purity of the final product which is
very useful in the pharmacy industry.

 The temperature and time in the crystallization are the most important features during the
crystallization process because they controlled the nucleation and the crystal growing. For that
reason, it’s important to consider the conditions of the experiment in order to improve the
results of the crystallization.