Aug. 27  2020  3  US 2020/0268679 Al  [0024]  The nanoparticles can have a Z-average particle  size of from 10 nm to 1000 nm  from 25 nm to 1200 nm   from 50 nm to 500 nm  from 75 nm to 400 nm  from 100 nm  to 350 nm  from 100 nm to 250 nm  or from 100 nm to 150  nm. The nanoparticles can have a polydispersity index (PDI)  of from 0.06 to 0.5  from 0.07 to 0.34  from 0.08 to 0.27   from 0.1 to 0.2  or from 0.12 to 0.18.  [0025]  The API and a supplemental hydrophobic com› pound can be co-encapsulated in the nanoparticles. For  example  the supplemental hydrophobic compound can be a  therapeutic  an imaging agent  or an agrochemical com› pound.  [0026]  The API can include gentamycin  polymyxin B   mastoporan 7  sub5  LL37  colistin  ecumicin  OZ439  oval› bumin  or lysozyme. The API can include an antimicrobial  small molecule  or example  an antimicrobial small mol› ecule having a molecular weight of less than 1000 Da. The  API can include an aminoglycoside  for example  a 4 6- disubstituted deoxystreptamine trisaccharide. The API can  include an oligopeptide  such as a linear oligopeptide or a  cyclic oligopeptide  which can have a molecular weight of  from 1000 Da to 2000 Da. The API can include a protein   such as an anionic protein or a cationic protein  which can  have a molecular weight of greater than 2000 Da.  [0027]  The IP reagent can include sodium dodecyl sulfate  (SDS)  sodium decyl sulfate (DS)  sodium dodecylbenzene  sulfonate (DBS)  sodium myristate (MA)  sodium oleate  (OA)  pamoic acid disodium salt (PA)  vitamin E succinate   or sodium dextran sulfate (DXS). The counterion can  include dodecyl hydrogen sulfate  decyl hydrogen sulfate   dodecylbenzene sulfonic acid  myristic acid  oleic acid   pamoic acid  vitamin E succinic acid  or dextran hydrogen  sulfate. The counterion can include a fatty acid  an alkyl  hydrogen sulfate  an alkylsulfonic acid  or an alkyl quater› nary ammonium cation.  [0028]  The polymer can include hydroxypropyl methyl› cellulose acetate succinate (HPMCAS)  polystyrene-block› polyethylene glycol  (PS-b-PEG)  or polycaprolactone› block-polyethylene glycol (PCL-b-PEG). The polymer can  include a block copolymer  for example an amphiphilic  block copolymer. The block copolymer can have a molecu› lar weight of about 10 kDa or less.  BRIEF DESCRIPTION OF THE DRAWINGS  [0029]  FIG.  1  illustrates the Mechanism of ion pairing› based Flash NanoPrecipitation. FNP of pre-ion paired APL  Hydrophilic active pharmaceutical ingredients are created as  a hydrophobic salt by pre-pairing the API with a hydropho› bic counterion. Pre-ion pairedAPis are dissolved in organic  solvent alongside an amphiphilic block-copolymer  and rap› idly micromixed against water. Hydrophobic API ion pairs  precipitate into NCs and self-assemble into NCs. FNP with  in situ ion pairing. Hydrophilic APis are dissolved in water  and rapidly micromixed against organic solvent containing  a hydrophobic API counterion and an amphiphilic block› copolymer. Ion pairing of the API occurs during mixing   producing a hydrophobic API ion pair that precipitates in the  presence of an amphiphilic block-copolymer  resulting in the  formation of NCs.  [0030]  FIG.  2  shows the chemical structure of gentamicin  (at top) and polymyxin B (at bottom)  hydrophilic active  pharmaceutical ingredients tested within the study presented  herein. Gentamicin (Log P=-4.21) is an aminoglycoside  having a molecular weight of 478 Da that functions by  [0038]  FIG. 7A provides a graph showing release rates  (fraction released as a function of time) of polymyxin B NCs  when using  1:  1 API to IP charge ratio for the IPs sodium  dodecyl sulfate (SDS)  sodium dodecylbenzene sulfonate  (DBS)  and sodium oleate (OA).  [0037]  FIG. 6C provides a graph of size distributions of  NPs formed with in situ ion pairing of polymyxin B using  the IPs sodium dodecyl sulfate (SDS)  sodium dodecylben› zene sulfonate (DBS)  pamoic acid disodium salt (PA)  and  sodium oleate (OA). Compositions of NC formulations are  given in Table 1.  [0036]  FIG. 6B provides a graph of size distributions of  NPs formed using polymyxin B as a pre-formed API:IP  complex using the IPs sodium dodecyl sulfate (SDS)  decyl  sulfate (DS)  sodium dodecylbenzene sulfonate (DBS)  and  pamoic acid disodium salt (PA). Compositions of NC for› mulations are given in Table 1.  [0035]  FIG.  6A  provides a graph of size distributions of  NPs formed using gentamycin as a pre-formed API:IP  complex using the IPs sodium dodecyl sulfate (SDS)  decyl  sulfate (DS)  sodium dodecylbenzene sulfonate (DBS)  and  pamoic acid disodium salt (PA). Compositions of NC for› mulations are given in Table 1.  [0034]  FIG.  SB  provides a graph illustrating the modeling  of API precipitation conditions by utilizing equation (10).  The fraction of API that is precipitated with varying satu› ration solubilities of the API:IP complex  and by varying the  amount of API in the reaction. The amounts of API and IP  included in the reaction are at a one to one ratio. [API]$_{0 }$ has  dimensions of M. Precipitation yields can be increased by  decreasing complex saturation solubility  by increasing com› plexation strength  or by increasing the concentration of the  reaction.  [0033]  FIG.  SA  provides a graph illustrating the modeling  of API precipitation conditions by utilizing equation (10).  The fraction of API that is precipitated with varying satu› ration solubilities of the API:IP complex and with varying  tendencies of complex formation ( complexation strength) is  shown. Saturation solubility is noted with [API:IP]sat and  has units of mo! L- 1 .  Complexation strength is noted with Ks  and has dimensions of mo1- 1  L- 1 .  The amounts of API and  IP included in the reaction are at a one-to-one ratio at 1 M.  [0032]  FIG.  4  provides a graph presenting the results of  screening of ion pair (IP) properties for FNP-based NC  assembly with polymyxin. The physical properties (pKa and  c Log P) of ion pairs that failed to precipitate APis (dia› monds)  that precipitated APis but failed to produce NCs  (circles)  and that precipitated APis and produced NCs  (squares) are shown. The following IPs that precipitated  APis and produced NCs are labeled: sodium oleate (OA)   pamoic acid disodium salt (PA)  sodium dodecylbenzene  sulfonate (DBS)  and sodium dodecyl sulfate (SDS).  [0031]  FIG.  3  shows ion pairs screened and tested within  the study presented herein. A wide variety of anionic salts  were used and paired against gentamicin and polymyxin B.  Salts that could precipitate APis into NCs in the FNC  process are named in bold. Salts that precipitated APis out  of water  but not into NCs in the FNC process are italicized.  inhibiting protein synthesis. Polymyxin B (Log P=-5.62) is  a macrocyclic cationic peptide having a molecular weight of  1302 Da that functions by forming pores on cell membranes.  Both gentamicin and polymyxin B are active against gram› negative bacteria. 