Amorphous lactose

Amorphous lactose
Origins and measurement
MCC
Starch
Lactose
Inhalation
Superdisintegrants
Summary
The presence of amorphous lactose in predominantly crystalline materials has several origins. It could
either be created deliberately as is the case in spray dried grade lactoses where it has an important
function in the properties. Or it is created during processing of lactose during crystallization and milling
processes. There are several techniques to assess the amorphous content, but they all have there own
advantages and disadvantages.
1
Introduction
Lactose can be obtained in several forms: crystalline and amorphous. The major crystalline forms are αlactose monohydrate and β-lactose anhydrous. Both are obtained by crystallization from aqueous
solution, α-lactose monohydrate by crystallizing a supersaturated solution below 93.5°C, β-lactose by a
drum drying technique at temperatures above 93.5°C. Several other crystalline forms of lactose are
described and characterized, such as anhydrous α-lactose or a α-β ‘mixed crystal’. Amorphous lactose is
a well described, but less characterized form of lactose. It has no crystal structure and it is a metastable
phase, meaning that the structure is expected to change in time.
2
Origins of amorphous lactose/way of preparation
Deliberate production of amorphous lactose can be done in several ways, these methods relay on the
removal of solvent (water) from a solution of lactose in such a way that the lactose can not crystallize. By
for instance freeze drying, the solution is frozen and the solvent is removed by sublimation. Due to the
frozen and immobilized matrix, lactose molecules lack the mobility to rearrange themselves into a
crystalline lattice. Spray drying is another way of producing amorphous lactose, but in this case water is
removed very fast from the lactose solution which limits the time lactose has to crystallize. It was found
that lactose produced by these two methods yields two amorphous materials that have very different
(1)
behavior. For instance, the gravimetric water absorption was completely different.
100
= H2O
= lactose
90
SD
80
70
Ts
60
Solution
Temperature [°C]
50
rubbery zone
40
30
20
solution
( crystals)
10
delay crystallisation
10 min.
0
1 hour
Tf
-10
1 day
FD
-20
ice and solution
Tg
-30
-40
-50
Glassy
solid state
Cg'
-60
0
5
10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
85
90
95
100
Total solids [%]
Figure 1: Phase diagram of lactose in water. Tf: freezing temperature, Tg: glass transition temperature, Ts: lactose
solubility. Paths for production of amorphous lactose by freeze drying and spray have been drawn, indicating the
differences between the two ‘kinds’ of amorphous lactose.
An application of amorphous lactose produced by spray drying is in tableting. For this material a
dispersion of fine lactose in water is spray dried. During the process, some of the lactose will dissolve in
the water phase. After the spray drying process, some of the dissolved material will remain in the
amorphous phase. The product consists of lactose crystals, bound together by amorphous lactose; the
(2)
content of the amorphous phase is dependent on the process but is in the order of 10%. During
tableting the ductile amorphous phase makes the spray dried highly compactable and yields tablets with
(3)
a high tensile strength. Crystallization of the amorphous fraction post tableting is beneficial to the tablet
strength.
Amorphous lactose, origins and measurement
3
Figure 2. SEM picture of Lactopress spray dried (LPSD)
Minor amounts of amorphous lactose can be present in predominantly crystalline lactose. This can be
caused by several reasons but two processes are most likely to have occurred in commercial lactoses:
during drying after the crystallization process or by milling processes.
Lactose is produced by crystallization from an aqueous solution of lactose. Adhering solvents after
filtration of the crystals cause dissolved lactose to remain at the surface of crystals. After drying, these
(4)
could form amorphous domains. Milling is known to be a source of amorphous lactose and the more
energetic the milling the more the crystal phases will be disrupted. Heavily milled types of lactose such
as micronized have been characterized to contain up to 10% amorphous content.
Although the amount of amorphous content could be low, its importance could be higher. Especially in
inhalation grade lactose the presence of it should be under control: it is an unstable phase and changes
(5, 6)
in this phase could cause changes in the function of lactose in the inhalation device.
3
Determination of amorphous content
(7)
Several methods exist in order to determine the amorphous content in lactose samples. A number of
these methods are based on the phase transition of amorphous to crystalline lactose, which is forced by
(8)
temperature and humidity. Buckton and Darcy described a method where a sample of lactose is first
dried until all moist in the amorphous phase is dried away, followed by a treatment of the sample at very
high humidity (~90% RH). This high humidity forces the amorphous lactose to absorb water and at
certain water content in the amorphous phase, the lactose becomes mobile enough to start crystallizing.
Because lactose crystallizes to the monohydrate form, drying of the crystallized sample will cause a
weight difference before and after the whole treatment. This weight difference is the additional water
molecule that accompanies each lactose molecule in the α-lactose monohydrate crystal lattice. From this
the amount of amorphous lactose that was present in the original sample can be calculated. The levels of
quantification of these types of techniques are in general around 0.5% amorphous content.
Calorimetric methods depend on the same principle of the gravimetric methods, i.e. that amorphous
lactose will crystallize when the temperature is around the glass transition temperature. The difference is
(9)
that these methods measure the energy of crystallization. For example, a DSC method that is capable
of measuring amorphous content concentrations as low as 0.5% utilizes the presence of acid casein as a
controlled source of water was reported. Upon heating a mixture of lactose sample with casein a
exothermic peak will show the crystallization event and the amorphous content can be calculated from
the area of this peak.
Both described techniques rely on the fact that amorphous lactose should crystallize. The gravimetric
and calorimetric methods demands that the crystallization should yield lactose monohydrate, which is not
(10)
necessarily the case. This will lead to deviations in the measured amount from the real amorphous
content.
Several other techniques have been reported such as spectroscopic techniques like Raman and X-ray
diffraction. Although these methods lack the disadvantage of the techniques that rely on recrystallization,
there sensitivity is in most cases not high enough.
4
Amorphous lactose, origins and measurement
References
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Amorphous lactose, origins and measurement
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DFE Pharma (#code/month year)
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Amorphous lactose, origins and measurement