TrpT

[digger]

Mar 23, 2018 8:19:34 GMT -5 bioexec25 said:

From Dr. Leone-Bay & colleagues: "The particles can be either crystalline or amorphous (Figure 2). Crystalline particles are prepared by a controlled, pH-induced crystallisation process in which FDKP nanocrystals self-assemble into microparticles".

www.mannkindcorp.com/Collateral/Documents/English-US/Innovation%20In%20Drug%20Delivery%20by%20Inhalation.pdf

I get the impression from reading that article that only the crystalline form can be used to deliver drugs. Formation of the crystal forms the lattice into which the drug is locked.

[Deleted]

digger This is a guess: That is unlikely since Liquidia's technology doesn't form crystals.

[digger]

Mar 23, 2018 9:23:01 GMT -5 @kastanes said:

digger This is a guess: That is unlikely since Liquidia's technology doesn't form crystals.

Right, I see on Liquidia's website it says "LIQ861
particles are a precise, uniform size (1µm) and trefoil pollen-like shape" and they're made from a mold of some sort.  But in the case FDKP, my impression was that as FDKP crystallized, the drug would get caught within the lattice of the crystal. In other words, you need to form the lattice to produce the inhalable final product, and that requires the crystalline form.  So the amorphous form wouldn't be useful for enhancing drug delivery.

[dreamboatcruise]

Mar 23, 2018 11:34:00 GMT -5 digger said:

Mar 23, 2018 9:23:01 GMT -5 @kastanes said:

digger This is a guess: That is unlikely since Liquidia's technology doesn't form crystals.

Right, I see on Liquidia's website it says "LIQ861
particles are a precise, uniform size (1µm) and trefoil pollen-like shape" and they're made from a mold of some sort.  But in the case FDKP, my impression was that as FDKP crystallized, the drug would get caught within the lattice of the crystal. In other words, you need to form the lattice to produce the inhalable final product, and that requires the crystalline form.  So the amorphous form wouldn't be useful for enhancing drug delivery.

Material from Mannkind definitely talks about using the amorphous form for drug delivery.  The process for manufacturing it involves creating a solution from a salt of FDKP and the API and then spray drying to form the amorphous particles.  I do not recall reading any of the details of what would determine which form is the better (or only viable) solution for a particular API.  If I were guessing, I might think it would have something to do with the size and electrostatic properties of the API.

@kastanes previously stated that amorphous is cheaper to produce compared to crystalline form.

Apparently stability of the two forms might vary from API to API.

"Development of formulations for dry-powder
inhalation combination products requires
some key considerations including stability and
particle architecture. Drug stability should be
evaluated in both crystalline and amorphous
particles"

(from www.ondrugdelivery.com/publications/OINDP%20April%202011/Mannkind.pdf)

[digger]

Mar 28, 2018 17:53:55 GMT -5 dreamboatcruise said:

Mar 23, 2018 11:34:00 GMT -5 digger said:

Right, I see on Liquidia's website it says "LIQ861
particles are a precise, uniform size (1µm) and trefoil pollen-like shape" and they're made from a mold of some sort.  But in the case FDKP, my impression was that as FDKP crystallized, the drug would get caught within the lattice of the crystal. In other words, you need to form the lattice to produce the inhalable final product, and that requires the crystalline form.  So the amorphous form wouldn't be useful for enhancing drug delivery.

Material from Mannkind definitely talks about using the amorphous form for drug delivery.  The process for manufacturing it involves creating a solution from a salt of FDKP and the API and then spray drying to form the amorphous particles.  I do not recall reading any of the details of what would determine which form is the better (or only viable) solution for a particular API.  If I were guessing, I might think it would have something to do with the size and electrostatic properties of the API.

@kastanes previously stated that amorphous is cheaper to produce compared to crystalline form.

Apparently stability of the two forms might vary from API to API.

"Development of formulations for dry-powder
inhalation combination products requires
some key considerations including stability and
particle architecture. Drug stability should be
evaluated in both crystalline and amorphous
particles"

(from www.ondrugdelivery.com/publications/OINDP%20April%202011/Mannkind.pdf)

But I think when it says "drug stability should be evaluated, " it just means that you have to make sure that the drug doesn't chemically react with the FDKP or undergo any other change that might alter its effect. 

The description of how FDKP works as a carrier implies that it must be put in an acid solution with the drug so when the FDKP crystallizes, it forms a lattice in which the drug is captured without any chemical changes, and then when exposed to the human neutral pH it dissolves and releases the drug unchanged. 

Using amorphous wouldn't make much sense.  How would amorphous transport the drug?  Just FDKP and drug wouldn't react if mixed; you'd just have a mix of FDKP and drug. 

[dreamboatcruise]

Mar 28, 2018 21:46:10 GMT -5 digger said:

Mar 28, 2018 17:53:55 GMT -5 dreamboatcruise said:

Material from Mannkind definitely talks about using the amorphous form for drug delivery.  The process for manufacturing it involves creating a solution from a salt of FDKP and the API and then spray drying to form the amorphous particles.  I do not recall reading any of the details of what would determine which form is the better (or only viable) solution for a particular API.  If I were guessing, I might think it would have something to do with the size and electrostatic properties of the API.

@kastanes previously stated that amorphous is cheaper to produce compared to crystalline form.

Apparently stability of the two forms might vary from API to API.

"Development of formulations for dry-powder
inhalation combination products requires
some key considerations including stability and
particle architecture. Drug stability should be
evaluated in both crystalline and amorphous
particles"

(from www.ondrugdelivery.com/publications/OINDP%20April%202011/Mannkind.pdf)

But I think when it says "drug stability should be evaluated, " it just means that you have to make sure that the drug doesn't chemically react with the FDKP or undergo any other change that might alter its effect. 

The description of how FDKP works as a carrier implies that it must be put in an acid solution with the drug so when the FDKP crystallizes, it forms a lattice in which the drug is captured without any chemical changes, and then when exposed to the human neutral pH it dissolves and releases the drug unchanged. 

Using amorphous wouldn't make much sense.  How would amorphous transport the drug?  Just FDKP and drug wouldn't react if mixed; you'd just have a mix of FDKP and drug. 

I can't personally vouch for the feasibility from my own expertise, but more than one Mannkind document talks about the process to create the amorphous form of a carrier particle... i.e. using a salt of FDKP mixed with the API into a solution and then sprayed dried, resulting in uniform sized particles containing both FDKP and the API.  It is a different manufacturing process from the one used for the crystalline form which you cite.