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Development of new routes
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‘Synthesis system
Focused Beam Reflectance Measurement (FBRM) |
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 FBRM
is an apparatus enabling real-time observation to measure particle
size distribution and the number of particles by quantification
with inline measurement. By monitoring the number of particles of
a particular size, highly sensitive and accurate quantification
of the changes occurring in liquid solution is possible. Crystal
polymorphs with different crystal shapes and sizes are a crucial
factor when obtaining pharmaceuticals, intermediates and organic
compounds in the crystal state. In order for drugs to be absorbed
by the human body and be effective, they should not be powder, encapsulated
or tablets. Drugs become effective when they penetrate the circulating
blood from the absorption site by changing state to solution liquid
after the process of break-down, dispersion and dissolution in the
gastrointestinal tract (within the buccal cavity and intestinal
tract). So, the crystals must be dissolved and their size and shape
govern the efficacy of the drug. In other words, the ability to
control a target crystal shape and size during recrystallization
is of paramount importance. Shiratori Pharmaceutical, employing
inline FBRM, carries out review experiments of different solvents,
temperatures and cooling times to develop a method of recrystallization
and purification with which mass production is possible. Additionally,
during mass production, since the response speed depending on dissolution
speed tends to be one of the major factors affecting the efficiency,
we confirm the dissolution by measuring the size and number of crystals.
Recrystallization, a process affecting the quality of the product,
is used even after confirming the final stage of crystallization
by inline monitoring to avoid degradation of yield and purity due
to scale-up. |
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| ‘Automatic synthesizer: "ChemiStation" |
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 Optimization
of reaction conditions is essential during laboratory-scale review
experiments and to decide whether shortening the period would significantly
affect the outcome at an early stage of the development. One ChemiStation
can handle five reactants simultaneously. Shiratori Pharmaceutical
owns four of them to improve the speed and efficiency of review experiments. |
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| ‘Automatic synthesizer:
200ml: four units, 1000ml: one unit |
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Automatic synthesizer: 200ml |
Automatic synthesizer: 1000ml |
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| When changing over from
laboratory scale to plant production, the key factors
are: reaction time, temperature, dripping time, pH, pressure,
reaction calorie and cooling/heating gradient. There are
many cases in which a successful synthesizing of reaction
fails when scaled up to plant production. Skills and know-how,
which cannot be expressed objectively in numbers, of the
person who conducts the experiment greatly contribute
to the result. Also, some failures come from unexpected
causes, such as longer time or unpredictable heat generation.
Therefore, we verify conditions which can be used to predict
and avoid failures at scale-up to produce consistent experiment
results and production quality irrespective of the operator.
In doing so, we collect detailed data for optimal mass
production by automating and quantifying every experimental
environment and procedure with an automatic synthesizer.
This automatic synthesizing system is quadruple and capable
of reactions ranging from -90C to +300C. |
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| ‘Microwave (MW) system: 30 units in a series |
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 The
MW system for synthesis is an apparatus for chemical reaction and
synthesis that uses MW energy characteristics. We use it for day-to-day
development of new reaction fields to explore the best reaction conditions
requiring only a few minutes for the reactant with delayed reaction
progress or requiring several dozen hours at high temperature. Reaction
by MW may produce advantageous results in terms of "green chemistry"
considering environmental harmonization since it requires no heating
medium, thus leading to reduction of synthesis at high speed and temperature,
suppression of by-product generation and decrease of waste. |
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| ‘Preparation system with an axial compression
column |
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 Separation
and purification are indispensable for isolating impurities, deciding
on composition and clarifying the generation mechanism when synthesizing
pharmaceuticals and products requiring high purity. After selecting
efficiency (separation ability, specimen burden and preparative isolation
time) and economy (type of filler, cost of eluting solvent and capability
per unit time) of separation, the procedure should be as follows:
choose internal diameter, length and filler type of the column suitable
for the specimen amount and particle diameter with a computer-controlled
column system by using an axial compression column; and automatic
preparative isolation of multiple impurities from chromatography patterns
with isocratic gradient conditions. For the isolated compound, we
decide the composition and use it in our everyday work for high-purity
optimization and high-yield synthesis. |
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| ‘Molecular distillation system and
precision distillation |
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Molecular distillation system |
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precision distillation |
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Molecular distillation is a depressurized distillation
technique which lessens the distance between the surfaces of
evaporation and condensation smaller than the average free path
of molecular steam, and conducts distillation under high vacuum
of10-3Torr.
Since this system adopts a centrifugal membrane (flowing down
as membrane onto the heating surface) and evaporation occurs
only from the surface of the substance, efficient distillation
is possible. It is used for precision distillation for materials
that cannot be distilled with normal depressurized distillation,
have a high boiling point or become unstable under heat. |
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