WO2018109000A1

WO2018109000A1 - Method of producing a powder of lactose

Info

Publication number: WO2018109000A1
Application number: PCT/EP2017/082605
Authority: WO
Inventors: Peter Wagner
Original assignee: Spx Flow Technology Danmark A/S
Priority date: 2016-12-13
Filing date: 2017-12-13
Publication date: 2018-06-21
Also published as: EP3555321A1

Abstract

Herein there is disclosed a method for controlling an amount of amorphous lactose in a dried lactose powder comprising: i) supplying a mass-flow of a slurry comprising a first amount of dissolved lactose and a first amount of crystals of α-lactose monohydrate, said slurry having a total-solids concentration TS and a slurry temperature, T_slurry, to a dryer for producing a lactose powder comprising amorphous lactose and crystals of α-lactose monohydrate at a first mass flowrate; ii) diverting a fraction, f, of said mass-flow of said slurry to a heater (2) where, in said heater, said fraction, f, of said mass-flow of said slurry is heated to a heating temperature, T_heat, before being redirected to said mass-flow of said slurry; and v) drying said slurry in a dryer (5) for producing a lactose powder.

Description

METHOD OF PRODUCING A POWDER OF LACTOSE FIELD

The present invention relates to methods of producing a powder of lactose from aqueous slurries comprising crystals of -lactose monohydrate and dissolved lactose, whereby improved control of the ratio of amorphous to crystalline lactose in the powdery lactose product is obtained.

BACKGROUND Lactose is an important by-product of the dairy industry with many important uses such as infant nutrition and in pharmaceutical products. It is a water soluble molecule present naturally in milk wherein it makes up 2-8% of the milk by weight.

Lactose in aqueous solution has two anomeric forms, Ga^¬ lactose and β-lactose which in solution are dynamically in equilibrium and can mutarotate to maintain their equilibrium.

In general, crystals of a-lactose (correctly a-lactose monohydrate) are obtained from aqueous solution by crystallization. In aqueous solution the a-form is less soluble than the β-form at a given temperature below approximately 93°C and the a-form reaches the point of supersaturation first and forms crystals of a-lactose monohydrate when crystallized from aqueous solution. Throughout the present disclosure no distinguishing will be made between crystals of α-lactose and crystals of a- lactose monohydrate, as the resulting product of crystallization from aqueous solution is always the Ga^¬ lactose monohydrate crystal form. The removal of -lactose from solution due to crystallization means that the proportion between a- and β-lactose changes, so that the solution contains more β- lactose than corresponding to their equilibrium. However, due to mutarotation the content of a-lactose is continuously replenished, thereby maintaining supersaturation and enabling crystallization to continue. This process will continue as long as the solution is supersaturated and will not stop until the saturation point is reached.

It is well known in the art, that 100% pure a-lactose monohydrate powder has basically no buffer effect regarding water activity, meaning that for practical purposes it does not absorb or desorb water. On the contrary, amorphous lactose has a significant buffer effect regarding water activity up to a point where the amorphous powder becomes unstable and crystalizes to a-lactose monohydrate while releasing water. It is therefore customary in the art to adjust the ratio of amorphous lactose to α-lactose monohydrate in dried lactose powders in order to control powder stability and shelf-life. Likewise, it is customary in the art to adjust the amount of amorphous lactose in spray dried lactose products intended as e.g. pharmaceutical excipients, wherein control of powder sphericity is essential, which control depends intrinsic on the ratio of the amount of amorphous lactose to the amount of crystalline a-lactose monohydrate present in the slurries from which the spray dried lactose product is manufactured.

It is well-known in the art (cf. e.g. Bolhuis, Kussendrager and Langridge in Pharmaceutical Technology: Excipients and Dosage Forms 2004, p. 26-31) , that the ratio of β-lactose to a-lactose is substantially unaltered in spray drying and that consequently, most, if not all, of the β-lactose present in solution will precipitate into the dried product as amorphous powder.

WO 2012/047122 describes a method of manufacturing a slurry comprising crystals of a-lactose monohydrate by concentration in an evaporator, by feeding a continuous stream of dissolved lactose to a process loop comprising a heat exchanger with a holding cell and the evaporator, wherein the slurry of a-lactose monohydrate crystals is created in the evaporator and subsequently removed by centrifugal clarification in a hydrocyclone above a certain cut-off size, allowing a slurry comprising crystals below the cut-off size to circulate the process loop. In this process, the ratio of β-lactose to α-lactose is determined by the operating temperature of the heat exchanger and the evaporator, but the slurry of crystals of a-lactose monohydrate led to a subsequent dryer is unaltered after passage of the hydrocyclone.

However, modern methods of manufacturing a-lactose monohydrate crystals, such as e.g. described in WO 2016/071397 A9, yield a-lactose monohydrate crystal- powders of very high purity and almost completely devoid impurities, but thereby, consequently, also almost completely devoid of the amorphous lactose necessary for controlling powder stability and shelf-life of e.g. spray dried or fluid bed dried powders .

In the art, control of the amount of amorphous lactose in dried lactose powder have traditionally been achieved by:

1) Reducing the purity of the final -lactose monohydrate crystals when washing the crystals, in order thereby to retain some of the beta lactose present in the solution in the crystallization tank. However, if this is done to an extend where it gives a significant effect, then this will also give high level of surface ash, since the ash concentration is high in the crystallization tank.

2) Reducing the efficiency of the separation of the crystals from the water, which will give more amorphous lactose on the surface of the crystals when entering the drying step and also to some extend give more amorphous lactose in the powder after drying, however this also means that significantly more energy will be required for evaporation of the water; or

3) Applying high heat early in the drying (e.g. in the first drying section in a fluid bed dryer) , to quickly dry the product thereby partially preventing the dissolved lactose entering with the liquid phase from crystalizing during the drying, so that more stays in amorphous form in the dried powder.

However, the above methods all have drawbacks, in particular with respect to high purity a-lactose monohydrate products, in form of increases in ash, particle size, etc.

There is thus a need for an effective way of adjusting the level of amorphous lactose in lactose powders comprising amorphous lactose and crystals of a-lactose monohydrate which do not give any important disadvantages. The below described process provides a simple and efficient method of controlling and increasing the amount of amorphous lactose on the surface of the -lactose monohydrate crystals without any significant disadvantages, such as the above disadvantages outlined above.

SUMMARY OF THE INVENTION

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1: Flow-diagram of the method of the invention. Figure 2: Exemplary process of the invention. Figure 3: Exemplary process of the invention. DETAILED DESCRIPTION

In accordance with the invention, there is detailed below a method for controlling an amount of amorphous lactose in a dried lactose powder comprising: i) supplying a mass-flow (MF) of a slurry comprising a first amount of dissolved lactose and a first amount of crystals of a-lactose monohydrate, said slurry having a total-solids concentration TS and a slurry temperature, Tsiurry, to a dryer for producing a lactose powder comprising amorphous lactose and crystals of a-lactose monohydrate at a first mass flowrate; ii) diverting a fraction, f, of said mass- flow of said slurry to a heater (2) where, in said heater (2), said fraction, f, of said mass-flow of said slurry is heated to a heating temperature, Theat, before being redirected to said mass-flow of said slurry; and v) drying said slurry in a dryer (5) for producing a lactose powder.

The general flow-diagram of the method of the invention is detailed in figure 1. It is intended that the source (1) for the lactose-slurry is a source (1), which can deliver a lactose-slurry which is ready for drying as a final, commercial product, such as a crystallization tank, since the problem of low amounts of dissolved β-lactose in the slurry does not arise in the process line before crystallization. E.g. the slurry extracted from the process loop in WO 2012/047122; which is a concentrated slurry at about the boiling point of water will have an amount of β- lactose dissolved in water of 90 g/100 g H2O , which is plenty for adequate control of the level of amorphous lactose in a dried lactose powder. On the other hand, lactose slurries exiting a crystallizer at e.g. only 10 °C will comprise practically zero dissolved β-lactose due to the preferential crystallization of -lactose, and therefore cannot provide the levels of β-lactose necessary for adequate control of amorphous lactose in subsequently dried lactose powders.

Accordingly, it is preferred that the lactose slurry for use with the present method shall comprise not more than 5 g/100 g H2O of dissolved β-lactose, not more than 3 g/100 g H2O of dissolved β-lactose, not more than 2 g/100 g H2O of dissolved β-lactose, preferably not more than 1 g/100 g H2O of dissolved β-lactose and most preferably not more than 0.5 g/100 g H2O of dissolved β-lactose. The process disclosed in WO 2016/071397 produces lactose powders with less than 5 g/100 g H2O of dissolved β-lactose. Further, there is disclosed a method according to a second embodiment of the invention wherein after step ii) , said fraction, f, of said mass-flow of said slurry (step iii) is held in a holding unit (3) for first holding time, thoid, sufficient to allow at least partial dissolution of said crystals of -lactose monohydrate in said holding unit, before being redirected to said mass-flow of said slurry.

Further, there is disclosed a method according to a third embodiment of the invention in accordance with either the first or second embodiments, wherein after either step ii) or step iii) respectively, said fraction, f, of said mass- flow of said slurry (step iv) is rapidly cooled to a cooled temperature, Tcooi, before being redirected as a supersaturated slurry or solution to said mass-flow of said slurry .

The effect of heating the slurry comprising crystals of Ga^¬ lactose monohydrate is that a part, and in some embodiments all, of the crystals of a-lactose monohydrate will dissolve at the heating temperature, Theat, and rapidly mutarotate to establish an equilibrium between dissolved β-lactose and a-lactose at the given heating temperature, whereby the ratio of β-lactose to α-lactose can be influenced in a known manner following the data provided in accordance with Table 1 below.

The amount of dissolved β-lactose and α-lactose at equilibrium in the slurry at the slurry temperature is known from Table 1, and the amount of dissolved β-lactose and α-lactose at equilibrium in the fraction of the slurry directed to the heater (2) at the slurry heating temperature is likewise known from Table 1, hence following common, well-established phase-equilibrium calculations, o it can easily be established how much dissolved β-lactose is redirected to the flow of unheated slurry. As the crystallization of a-lactose monohydrate is a slow process, the additional amount of dissolved β-lactose supplied by heating the aforementioned fraction of mass-flow of the slurry to the remaining mass-flow of the slurry (MF-f) can now be reliably controlled, and hence, since the amount of dissolved β-lactose in the slurry is determinant for the amount of amorphous lactose in the final, dried powder, the ratio of amorphous lactose to crystals of a-lactose monohydrate in the dried powder can be controlled to a high precision in the method, when starting from a known starting point, e.g. in accordance with the data of Table 1.

In Table 1 solubility and reaction rate parameters are given for a- and β-lactose for the temperature interval from 0°C to 100°C. It can be seen from the table that the ratio of β-lactose to α-lactose at equilibrium decreases linearly with temperature, whereas the mutation rate of β- lactose to α-lactose is accelerated by increasing the temperature above 30°C. As the crystallization of a-lactose monohydrate is favored when the temperature is below 30 °C it is preferable to keep the crystallization temperature below 30 °C and the mutarotation temperature above 30 °C.

When implementing a mutarotation temperature, the skilled person can be guided by the values of Table 1. As can be seen from the table, once 40°C is reached mutarotation rate is significantly improved and above 60°C conversion is very fast and holding time of only a few minutes give significant mutarotation. As such, short retention times are possible already when the temperature in the holding unit is at 40°C. Upwards in a closed or iso-volumeteric system mutarotation temperatures may exceed 100°C and a mutarotation temperature of about 110°C, of 120°C, of 140°C or even of about 160°C is possible in the method. However, under normal conditions the mutarotation temperature is contemplated to be from 40°C to 100°C, more preferably from 50°C to 90°C and most preferably from 60°C to 80°C. It is preferred in the method of the invention, that the method shall be performed under iso-volumetric conditions.

The heater (2) for heating the mentioned first volume from the crystallization temperature, T_si_urry, to the mutarotation temperature, Theat, is preferably a heat exchanger for continuous operation or a boiler for discontinuous operation .

The holding unit (3) can be constructed according to normal principles as is known to the skilled person.

The cooler (4) for cooling said first volume from the mutarotation temperature, Theat, to the crystallization temperature, T_si_urry, is preferably a heat exchanger for continuous operation or a cooler for discontinuous operation.

Table 1 - Solubility and reaction rate parameters for a- and β-lactose The skilled person will know that it is possible to combine two or more of the above process units of the mutarotation loop system (100) without departing from the basic principles of the invention. E.g. the heater (2) and the holding unit (3) could be combined into one element, e.g. a boiler or a heat exchanger with a holding unit, and also the cooler (4) could be combined into this sequence, e.g. as a holding unit (3) and a cooler (4), or a heat exchanger or boiler capable of heating, holding and cooling. The mere fact that a single process unit may perform one or several of the process steps associated with the method of the invention does not change the nature of the method. Rather it reduces equipment footprint and is beneficial.

Figure 2 details a preferred embodiment of the present invention, wherein a single heat exchanger with a holding- cell is detailed (Figure 2A) . The heat exchanger allows for the heated solution to cool be counter flow in the heat exchanger, whereby both energy and equipment footprint is saved. As can be seen from the exemplary calculation (Figure 2B) , the amount of dissolved β-lactose is raised in the process according to the method from effectively 0 g/100 g H2O to 14 g/100 g H2O under the given temperature conditions. Since this level is more than adequate for controlling the amount of amorphous lactose in the resulting dried powders, a flow controller can be installed to adjust the return flow (and hence the over-all flow) and thereby the amounts of added β-lactose. Under production conditions, it is generally easier to operate the heater (2), respectively as in the example, the heat exchanger with holding cell and counter flow cooling, at a constant temperature and to adjust the flow to provide the desired amounts of dissolved β-lactose for the intended levels of amorphous lactose in subsequently dried powders, rather than continuously adapting the process temperature to meet varying demands on the levels of amorphous lactose in the dried powders .

A dryer according to the invention can be e.g. a fluid bed dryer or a spray dryer as are known in the art of producing lactose powders from lactose slurries. In such dryers, it is a persistent problem, due to the statistical nature of the drying process, that an undersized fraction of powder is produced, in the art called fines. Such fines can be tedious to recycle but can, in the present method, find advantageous use. Figure 3 details this aspect of the invention in greater detail. Herein, the dried fines are mixed into the fraction of the lactose comprising slurry diverted from the mass- flow of the same slurry. Thereby the content of solid lactose in the slurry intended for heating is increased, permitting more β-lactose to be produced according to the method, while at the same time limiting the amount of slurry that has to be diverted in accordance with the method to a minimum. It is, off course, possible to suspend the fines in water, thus using this suspension as the slurry for use with the invention, however, this is not preferred as it increases the amounts of water which must subsequently be removed in the dryer. Rather, by suspending the fines in the slurry intended for drying, iso-volumetricity is maintained and the energy cost of drying is kept to a minimum.

Hence, in an embodiment of the present invention there is disclosed a method according to any of the preceding embodiments, wherein fines obtained by drying a slurry prepared according to any of these preceding embodiments in said dryer (5) for producing a lactose powder are admixed to said fraction, f, of said mass-flow of said slurry, prior to said fraction, f, of said mass-flow of said slurry entering said heater (2) .

Example 1 :

Crystals were dried after washing using 200 1/h of washing water in the sieve. In this product the Aw increased from 0,13 to 0,48 over 48 hours in a sealed container (thin line) . Then during drying of the same crystallization tank the washing water addition to the sieve was stopped and instead 100-150 1/h of pasteurized sieve water was added in the sieve. A sample from this product was taken 3½ hour later and in this sample Aw increased from 0,08 to 0,10 over 48 hours in a sealed container (thick line) .

Example 2 :

Crystals were dried where 150-200 1/h of pasteurized sieve water was added in the sieve. In this product the Aw increased from 0,08 to 0,11 over 48 hours in a sealed container (thick line) . Then the pasteurized sieve water was stopped and instead 200 1/h of washing water was added in the sieve. A sample from this product was taken 2 hours later, while still drying on the same crystallization tank. In this sample Aw increased from 0,11 to 0,18 over 48 hours in a sealed container (thin line) .

Both tests showed significant effect on the Aw buffer of the product, however it can be speculated if the effect is underestimated in the 2^nd example due to 2 hours not being sufficient to fully flush out the powder with pasteurized sieve water from the fluid bed. CLOSING COMMENTS

The term "comprising" as used in the claims does not exclude other elements or steps. The term "a" or "an" as used in the claims does not exclude a plurality. A single processor or other unit may fulfill the functions of several means recited in the claims. Although the present invention has been described in detail for purpose of illustration, it is understood that such detail is solely for that purpose, and variations can be made therein by those skilled in the art without departing from the scope of the invention.

Claims

CLAIMS :

1. Method for controlling an amount of amorphous lactose in a dried lactose powder comprising:

i) supplying a mass-flow of a slurry comprising a first amount of dissolved lactose and a first amount of crystals of -lactose monohydrate, said slurry having a total-solids concentration TS and a slurry temperature, Tsiurry, to a dryer for producing a lactose powder comprising amorphous lactose and crystals of a-lactose monohydrate at a first mass flowrate ;

ii) diverting a fraction, f, of said mass-flow of said slurry to a heater (2) where, in said heater, said fraction, f, of said mass-flow of said slurry is heated to a heating temperature, Theat, before being redirected to said mass-flow of said slurry; and v) drying said slurry in a dryer (5) for producing a lactose powder.

2. A method according to claim 1 wherein, after step ii) , said fraction, f, of said mass-flow of said slurry (step iii) is held in a holding unit (3) for first holding time, thoici, sufficient to allow at least partial dissolution of said crystals of a-lactose monohydrate in said holding unit, before being redirected to said mass-flow of said slurry.

3. A method according to either claim 1 or claim 2, wherein after either step ii) or step iii) respectively, said fraction, f, of said mass-flow of said slurry (step iv) is rapidly cooled to a cooled temperature, Tcooi, before being redirected as a supersaturated slurry or solution to said mass-flow of said slurry. A method according to any of the preceding claims, wherein fines obtained by drying a slurry prepared according to any of the preceding claims in said dryer (5) for producing a lactose powder are admixed to said fraction, f, of said mass-flow of said slurry prior to said fraction, f, of said mass-flow of said slurry entering said heater (2) .