US 12,000,915 B2 · Method for conducting solid state NMR on macromolecule-containing solid state formulations

Abstract

Disclosed herein is a method of conducting direct detection 1H solid state NMR (“ssNMR”) on a macromolecule-containing solid state formulation. The method includes conducting a 1H spin-lattice relaxation time (“T1”) experiment on the solid state formulation at various temperatures to generate a T1 value at each temperature, converting the T1 values to 1H spin-lattice relaxation rate (“R1”), and plotting R1 versus temperature to generate a relaxation rate curve for the solid state formulation. The relaxation rate curve can be analyzed to determine the molecular mobility of the macromolecule in the solid state formulation, the degree of aggregation in the solid state formulation, and/or the stability of the solid state formulation.

Claims20

Dependent claims

A method of conducting direct detection 1H solid state NMR (“ssNMR”) on a macromolecule-containing solid state formulation, the method comprising:

(a) equilibrating a solid state formulation comprising a macromolecule at a first temperature;
(b) conducting a 1H spin-lattice relaxation time (“T1”) experiment on the solid state formulation at the first temperature using direct detection 1H ssNMR to generate at least three free induction decay (“FID”) plots at the first temperature, wherein the T1 experiment comprises baseline suppression and a saturation recovery sequence having at least three variable delay times from which each FID plot is generated;
(c) equilibrating the solid state formulation at a second temperature, and repeating step (b) at the second temperature to generate at least three FID plots at the second temperature;
(d) equilibrating the solid state formulation at a third temperature, and repeating step (b) at the third temperature to generate at least three FID plots at the third temperature;
(e) generating a saturation recovery curve at each temperature;
and
(f) fitting each saturation recovery curve to a nonlinear regression equation to generate a T1 value at each temperature.

4 more elements

A method of selecting a macromolecule-containing solid state formulation among a group of test macromolecule-containing solid state formulations, the method comprising:

(I) generating a relaxation rate curve for each macromolecule-containing solid state formulation in the group of test macromolecule-containing solid state formulations;
wherein the relaxation rate curve for each macromolecule-containing solid state formulation is generated by:
(a) equilibrating the solid state formulation at a first temperature;
(b) conducting a 1H spin-lattice relaxation time (“T1”) experiment on the solid state formulation at the first temperature using direct detection 1H ssNMR to generate at least three free induction decay (“FID”) plots at the first temperature, wherein the T1 experiment comprises baseline suppression and a saturation recovery sequence having at least three variable delay times from which each FID plot is generated;
(c) equilibrating the solid state formulation at a second temperature, and repeating step (b) at the second temperature to generate at least three FID plots at the second temperature;
(d) equilibrating the solid state formulation at a third temperature and repeating step (b) at the third temperature to generate at least three FID plots at the third temperature;
(e) generating a saturation recovery curve at each temperature;
(f) fitting each saturation recovery curve to a nonlinear regression equation to generate a T1 value at each temperature;
(g) converting each T1 value to 1H spin-lattice relaxation rate (“R1”), and
(h) plotting R1 versus temperature to generate a relaxation rate curve for the solid state formulation;
(II) comparing the maximum R1 peak value of each curve, the temperature of the maximum R1 peak of each curve, the width of the maximum R1 peak of each curve, or a combination thereof;
and
(III) selecting the solid state formulation which has the lowest maximum R1 peak value, the highest temperature of the maximum R1 peak, or the narrowest R1 peak width.

10 more elements

A method of selecting a formulation excipient for use in a macromolecule-containing solid state formulation, the method comprising:

(I) generating a relaxation rate curve for each macromolecule-containing solid state formulation in a group of test macromolecule-containing solid state formulations, each formulation having a different composition of excipients, a different amount of one or more excipients, or both;
wherein the relaxation rate curve for each macromolecule-containing solid state formulation is generated by:
(a) equilibrating the solid state formulation at a first temperature;
(b) conducting a 1H spin-lattice relaxation time (“T1”) experiment on the solid state formulation at the first temperature using direct detection 1H ssNMR to generate at least three free induction decay (“FID”) plots at the first temperature, wherein the T1 experiment comprises baseline suppression and a saturation recovery sequence having at least three variable delay times from which each FID plot is generated;
(c) equilibrating the solid state formulation at a second temperature, and repeating step (b) at the second temperature to generate at least three FID plots at the second temperature;
(d) equilibrating the solid state formulation at a third temperature, and repeating step (b) at the third temperature to generate at least three FID plots at the third temperature;
(e) generating a saturation recovery curve at each temperature;
(f) fitting each saturation recovery curve to a nonlinear regression equation to generate a T1 value at each temperature;
(g) converting each T1 value to 1H spin-lattice relaxation rate (“R1”), and
(h) plotting R1 versus temperature to generate a relaxation rate curve for the solid state formulation;
(II) comparing the maximum R1 peak value of each curve, the temperature of the maximum R1 peak of each curve, the width of the maximum R1 peak of each curve, or a combination thereof;
and
(III) selecting an excipient that is present in the solid state formulation that has the lowest maximum R1 peak value, the highest temperature of the maximum R1 peak, or the narrowest R1 peak width.

10 more elements

Dependencies are inferred from the claim text.

Method for conducting solid state NMR on macromolecule-containing solid state formulations

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Method for conducting solid state NMR on macromolecule-containing solid state formulations

Life of this patent

Abstract

Claims20